7-acyl-3-(substituted carbamoyloxy) cephem compounds

ABSTRACT

A 7-acyl-3-substituted carbamoyloxy cephem compound represented by the following formula (1): ##STR1## wherein A means a --CH═ or --N═ group; R 1  denotes a hydroxyl, lower alkoxyl, fluorine-substituted lower alkoxyl or protected hydroxyl group; R 2  and R 3  are the same or different and individually represent a lower alkyl, hydroxyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl group or cyano-substituted lower alkyl group, R 2  is a hydrogen atom and R 3  is a lower alkoxyl or alkyl group optionally substituted by one or more halogen atoms, or the group ##STR2## means a 4-6 membered heterocyclic group, which contains one nitrogen atom, or a morpholino group, said heterocyclic group or morpholino group being optionally substituted by one or more lower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl groups; and R 4  denotes a carboxyl or protected carboxyl group; or a pharmaceutically acceptable salt thereof; and a process for the preparation thereof; as well as an antibacterial composition containing the above cephem compound.

This is a continuation application of Ser. No. 08/209,484, filed Mar.14, 1994; which is a continuation of now abandoned Ser. No. 07/789,669,filed Nov. 8, 1991.

BACKGROUND OF THE INVENTION

1) Field of the Invention

This invention relates to 3-(substituted carbamoyloxy)-3-cephemderivatives, novel antibacterial compositions having excellent effectsas drugs, and a process for their preparation.

2) Description of the Related Art

Japanese Patent Application Laid-Open (Kokai) No. 34794/1978 disclosesunsubstituted or lower-alkyl-substituted 3-carbamoyloxy-3-cephemderivatives including the compounds represented by the followingformula: ##STR3## wherein Y means a hydrogen atom or a nucleophilecompound residuum.

In addition, Japanese Patent Application No. 44714/1989 discloses thecompounds represented by the following formula: ##STR4## wherein R⁶means an amino group or an acylamino group, R⁷ denotes a carboxyl groupor a protected carboxyl group, the group represented by the formula##STR5## represents a di(lower) alkylamino group, a (lower) alkylaminogroup, a saturated, 5- or 6-membered, heterocyclic (lower) alkylaminogroup containing 1-4 nitrogen atoms, said alkylamino group beingoptionally substituted by one or more lower alkyl groups, or asaturated, 5- or 6-membered heterocyclic group containing 2-4 nitrogenatoms, said heterocyclic group being optionally substituted by one ormore lower alkyl or hydroxy(lower)alkyl groups, X¹ is --S-- or ##STR6##and the dotted line indicates a 2- or 3-cephem ring.

Further, Japanese Patent Publication No. 46474/1991 discloses cephemcompounds represented by the following formula: ##STR7## wherein R¹ isan amino or hydroxyl group which may optionally be protected, R³ is ahydrogen atom, R⁵ is a hydroxyl group or a substituted or unsubstitutedalkoxyl group, R⁸ is a hydrogen atom, Q denotes a carbon-carbon linkagefor the formation of a 3- substituted-3-cephem-4-carboxylic acid, and Rrepresents an ester residuum.

Several types of semisynthetic cephalosporins are now used for thetreatment of various infectious diseases. None of them are, however,satisfactory as antibacterial agents which have strong antibacterialactivities and, in particular, are orally-dosable.

SUMMARY OF THE INVENTION

An object of the present invention is therefore to provide anantibacterial composition which has strong antimicrobial activities and,moreover, is orally dosable.

As a result of an extensive investigation, the present inventors havefound that certain novel 3-substituted carbamoyloxy-3-cephem derivativeshave excellent antibacterial activities against various pathogenic fungiand their pharmacologically-protected derivatives are promptly absorbedthrough the digestive tract, form non-ester derivatives immediatelyafter their absorption and are hence useful as antibacterialcompositions for oral administration, leading to the completion of thepresent invention.

The present invention therefore provides a 7-acyl-3-substitutedcarbamoyloxy-3-cephem compound represented by the following formula (1),a pharmaceutically acceptable salt thereof, a preparation processthereof and an antibacterial composition and an intermediate comprisingthe same: ##STR8## wherein A means a --CH═ or --N═ group; R¹ denotes ahydroxyl group, a lower alkoxyl group, a fluorine-substituted loweralkoxyl group or a hydroxyl group protected by a protecting group; R²and R³ are the same or different and individually represent a loweralkyl group, a hydroxyl-substituted lower alkyl group, acarbamoyl-substituted lower alkyl group or a cyano-substituted loweralkyl group, R² is a hydrogen atom and R³ is a lower alkoxyl group or alower alkyl group which may optionally be substituted by one or morehalogen atoms, or the group represented by the formula ##STR9## means a4-6 membered heterocyclic group, which contains one nitrogen atom, or amorpholino group, said heterocyclic group or morpholino group beingoptionally substituted by one or more lower alkyl, hydroxyl and/orhydroxyl-substituted lower alkyl groups; and R⁴ denotes a carboxyl groupor a carboxyl group protected by a protecting group, or apharmaceutically acceptable salt thereof; its preparation process; anantibacterial composition comprising the compound or salt; and anintermediate for the compound.

The 7-acyl-3-substituted carbamoyloxy-3-cephem compound (1) and itspharmaceutically-acceptable salts have strong antibacterial activitiesand are orally dosable.

DETAILED DESCRIPTION OF THE INVENTION

In the above formula (1), examples of the lower alkoxyl group orfluorine-substituted lower alkoxyl group represented by R¹ include C₁₋₄alkoxyl groups and fluorine-substituted C₁₋₄ alkoxyl groups, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, monofluoromethoxy,difluoromethoxy, 2-monofluoroethoxy, 2,2-difluoroethoxy, and2,2,2-trifluoroethoxy.

The protecting group in "the protected hydroxyl group" represented by R¹is an easily-removable hydroxyl-protecting group, including, forexample, a protecting group removable under relatively mild conditions,such as formyl, acetyl, chloroacetyl, methoxyacetyl, phenoxyacetyl,benzoyl, ethoxycarbonyl, p-nitrophenoxycarbonyl, tetrahydropyranyl,tetrahydrothiofuranyl, trityl, methoxymethyl, ethoxymethyl,trimethylsilyl, t-butyldimethylsilyl or t-butyl. Of these, acetyl andtrityl are preferred.

Illustrative of the lower alkyl, hydroxyl-substituted lower alkyl,carbamoyl-substituted lower alkyl and cyano-substituted lower alkylgroups represented by R² and R³ in the formula (1) include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxybutyl, carbamoylmethyl,2-carbamoylethyl, 3-carbamoylpropyl, 2-cyanoethyl, 3-cyanopropyl, and2-cyanopropyl. The term "the lower alkyl group" as used in thedefinition for R³ that "R₂ is a hydrogen atom and R₃ is a lower alkoxylgroup or a lower alkyl group which may optionally be substituted by oneor more halogen atoms" includes alkyl groups such as described above,with a methyl group and an ethyl group being preferred. The loweralkoxyl group is similar to that defined for R¹. Exemplary halogen atomsinclude fluorine, chlorine and iodine, with fluorine atom beingpreferred. The number of halogen atoms as substituents can range from 1to 3.

On the other hand, examples of the 4-6 membered heterocyclic group,which contains one nitrogen atom, and morpholinyl group--saidheterocyclic group and morpholinyl group being represented by theformula ##STR10## and being optionally substituted--include thefollowing groups: ##STR11## wherein R¹⁰ represents a hydrogen atom or alower alkyl, hydroxyl or hydroxyl-substituted lower alkyl group.Examples of the lower alkyl group include methyl, ethyl and propyl,while examples of the hydroxyl-substituted lower alkyl group includehydroxymethyl and 2-hydroxyethyl.

As the group ##STR12## --NHCH₃ and --N(CH₃)₂ are preferred, with thelast group being more preferred.

Illustrative of the protecting group for the carboxyl group-representedby R⁴ include lower alkyl groups such as methyl, ethyl and t-butyl;lower alkyl groups substituted by one or more substituted orunsubstituted phenyl groups such as p-methoxybenzyl, p-nitrobenzyl,3,4-dimethoxybenzyl, diphenylmethyl, trityl or phenethyl; halogenatedlower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl;lower-alkanoyloxy-lower-alkyl groups such as pivaloyloxymethyl,acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and2-pivaloyloxyethyl; higher-alkanoyloxy-lower-alkyl groups such aspalmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl;lower-alkoxycarbonyloxy-lower-alkyl groups such asmethoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl,1-(t-butoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl and1-(isopropoxycarbonyloxy)ethyl; carboxy-lower-alkyl groups such ascarboxymethyl and 2-carboxyethyl; heterocyclic groups such as3-phthalidyl; benzoyloxy-lower-alkyl groups such as4-glycidyloxybenzoyloxymethyl and4-[N-(t-butoxy-carbonyl)glycyloxy]benzoyloxymethyl, saidbenzoyloxy-lower-alkyl groups optionally containing one or moresubstituent groups; (substituted dioxolene)-lower-alkyl groups such as(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substitutedlower-alkanoyloxy-lower-alkyl groups such as 1-cyclohexylacetyloxyethyl;and cycloalkyloxycarbonyloxy-lower-alkyl groups such as1-cyclohexyloxycarbonyloxyethyl.

In effect, any protecting group can be used as long as it can be removedby any means to form a carboxylic group. Preferred examples of theprotecting group include 1-(isopropyloxycarbonyloxy)ethyl group,1-(ethoxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethylgroup, pivaloyloxymethyl group and isopropyloxycarbonyloxymethyl group,with 1-(isopropyloxycarbonyloxy)ethyl group being more preferred.

Further, illustrative of the pharmaceutically acceptable salt includealkali metal salts such as the sodium and potassium salts; the ammoniumsalt; quaternary ammonium salts such as the tetraethylammonium andbetaine salts; alkaline earth metal salts such as the calcium andmagnesium salts; inorganic acid salts such as the hydrochloride,hydrobromide, hydroiodide, sulfate, carbonate and bicarbonate; organiccarboxylates such as the acetate, maleate, lactate and tartrate;organosulfonates such as the methanesulfonate, hydroxymethanesulfonate,hydroxyethanesulfonate, taurine salt, benzenesulfonate andtoluenesulfonate; amino acid salts such as the arginine salt, lysinesalt, serine salt, aspartate, glutamate and glycine salt; and aminesalts such as the trimethylamine salt, triethylamine salt, pyridinesalt, procaine salt, picoline salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt.

The compound of the present invention represented by the formula (1) canbe prepared, for example, by the following processes:

Preparation Process 1

The compound represented by the formula (1) or a salt thereof can beobtained by reacting a compound represented by the following formula:##STR13## wherein R², R³ and R⁴ have the same meanings as defined aboveor a salt thereof, with a compound represented by the following formula(3): ##STR14## wherein A and R¹ have the same meanings as defined above,and R⁶ represents an amino group or an amino group protected by aprotecting group, or a reactive acid derivative thereof or a saltthereof, and if necessary, removing the protecting group of the amino,carboxyl or hydroxyl group or protecting the carboxyl group with aprotecting group.

Examples of the amino-protecting group represented by R⁶ includecarbamoyl groups, aliphatic acyl groups, aromatic-ring-containing orheterocyclic-ring-containing acyl groups, sulfonyl groups andbenzilidene groups.

Illustrative of the acyl group and the sulfonyl group include alkanoylgroups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl and pivaloyl; alkoxycarbonyl groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl andhexyloxycarbonyl; aralkoxycarbonyl groups such as benzyloxycarbonyl andphenethyloxycarbonyl; alkanesulfonyl groups such as mesyl,ethanesulfonyl, propanesulfonyl, isopropanesulfonyl and butanesulfonyl;arenesulfonyl groups such as benzenesulfonyl and toluenesulfonyl; aroylgroups such as benzoyl, toluoyl, naphthoyl, phthaloyl andindanecarbonyl; aralkanoyl groups such as phenylacetyl andphenylpropionyl; aryloxyalkanoyl groups such as phenoxyacetyl andphenoxypropionyl; heterocyclic carbonyl groups such as furoyl, thenoyland nicotinoyl; heterocyclic glyoxyloyl such as thienylglyoxyloyl andthiazolylglyoxyloyl; and heterocyclic alkanoyl groups such as thienyland thiazolylacetyl. These groups may contain one or more suitablesubstituents, for example, halogens such as chlorine, bromine, iodineand fluorine; nitro groups; amino groups; alkanoylamino groups such asformylamino and acetylamino groups; cyano groups; alkyl groups such asmethyl, ethyl, propyl, isopropyl and butyl; alkenyl groups such as vinyland allyl; and groups represented by the formula ═N--OR₅ wherein R₅means a hydrogen atom; an alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, pentyl or hexyl; an alkenyl group such as vinyl orpropenyl; or an alkynyl group such as ethynyl or propynyl.

Illustrative of the benzylidene group includes benzylidene group,p-nitrobenzylidene group, m-nitrobenzylidene group,3,4-methylenedioxybenzylidene group and m-chlorbenzylidene group.

The compound (3) may be reacted in the presence of a condensing agent [acarbodiimide (N,N'-dicyclohexylcarbodiimide or the like), a carbonylcompound (carbonyldiimidazole or the like), an isoxazolium salt, or anacylamino compound (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline orthe like)]. Usable examples of its reactive acid derivative include acidanhydrides [symmetric acid anhydrides, mixed acid anhydrides (mixed acidanhydrides of mineral acids (phosphoric acid, sulfuric acid, carbonatehalf-esters or the like) and organic acids (alkanoic acids, aralkanoicacids, sulfonic acids or the like), etc.], acid halides, active esters[esters with N-hydroxy compounds (esters with N-hydroxysuccinimide orN-hydrophthalimide)], thiol esters (aralkylthiol esters, heterocyclicthiol esters, etc.), and aryl esters (phenyl ester, halophenyl esters,nitrophenyl esters, etc.).

The above reaction can be conducted at a reaction temperature of from-50° C. to +50° C. in an inert solvent such as dichloromethane,chloroform, tetrahydrofuran, acetone, ethyl acetate, methanol, ethanol,dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene or hexane.

The removal of each protecting group, the protection of a carboxyl groupwith a protecting group and the salt-forming reaction can be performedby methods known per se in the art.

The deprotection of the protected carboxyl group can be effected byhydrolysis in the presence of an acid. Here, preferred examples of theacid include inorganic acids such as hydrochloric acid, hydrobromic acidand sulfuric acid; organic acids such as formic acid, acetic acid,trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid;and Lewis acids such as boron trifluoride, aluminum trichloride, stannicchloride, ferric chloride, titanium tetrachloride an zinc chloride. Itis preferred to conduct the reaction in the presence of a cationscavenger such as anisole, if necessary.

The hydrolysis is generally conducted in an inert solvent such as water,methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide,dioxane or methylene chloride, or in a mixed solvent of two or more ofsuch inert solvents. The acids exemplified above can be used as asolvent. Although the reaction can be conducted generally at -78° C. to80° C., it is preferred to conduct it at a temperature ranging from icecooling to room temperature.

When R⁴ represents a carboxyl group or a salt thereof, the protectionmay be conducted by a method known per se in the art. For instance,esterification can be performed by the reaction with an alcohol-reactivederivative after optional conversion into an alkali metal salt or anorganic amine salt.

The conversion into the alkali metal salt is carried out using an alkalimetal salt of an organic acid such as sodium acetate, potassium acetate,sodium 2-ethylhexanonate, potassium 2-ethylhexanonate; an alkali metalhydroxide such as sodium hydroxide or potassium hydroxide; or an alkalimetal carbonate such as sodium carbonate, potassium carbonate or sodiumhydrogencarbonate; or the like. The conversion into the organic aminesalt can be carried out using trimethylamine, triethylamine,dichlorohexylamine or pyridine.

The reaction is generally conducted in an inert solvent such as water,methanol, ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide,dioxane, methylene chloride, ethyl acetate, methyl acetate oracetonitrile or in a mixed solvent of two or more of such inertsolvents.

The reaction with the alcohol-reactive derivative is generally conductedin an inert solvent such as water, methanol, ethanol, propanol,N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran,dioxane, methylene chloride, ethyl acetate, methyl acetate,acetonitrile, benzene or toluene; or in a mixed solvent of two or moreof such inert solvents. The reaction can be conducted generally at -78°C. to 80° C., but preferably at a temperature ranging from ice coolingto room temperature.

The removal of the protecting group from the protected amino group canbe conducted in the presence of an acid according to a common method.Preferred examples of the acid include inorganic acids such ashydrochloric acid, hydrobromic acid and sulfuric acid; and organic acidssuch as formic acid, acetic acid, trifluoroacetic acid, methanesulfonicacid and p-toluenesulfonic acid.

The reaction is conducted generally in an inert solvent such as water,methanol, ethanol, propanol, N,N-dimethylformamide,N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane or methylenechloride; or in a mixed solvent of two or more of such inert solvents.The reaction can be conducted generally at -50° C. to 50° C., butpreferably at a temperature ranging from ice cooling to roomtemperature.

Preparation Process 2

The compound represented by the following formula (5): ##STR15## whereinR², R³, R⁴ and ##STR16## have the same meanings as defined above or asalt thereof can be obtained by reacting the compound represented by thefollowing formula (4): ##STR17## wherein R², R³, R⁴ and ##STR18## havethe same meanings as defined above and X represents a halogen atom or asalt thereof with thiourea, and, if necessary, removing the protectinggroup of the carboxyl group or protecting the carboxyl group with aprotecting group.

The reaction is generally conducted in an inert solvent such as water,methanol, ethanol, propanol, N,N-dimethylformamide,N,N-dimethylacetamide, formic acid, acetic acid, acetone,tetrahydrofuran, dioxane, methylene chloride, ethyl acetate, methylacetate, acetonitrile, benzene or toluene; or in a mixed solvent of twoor more of such inert solvents. The reaction can be conducted generallyat -78° C. to 80° C., but preferably at a temperature ranging from icecooling to room temperature.

Preparation Process 3

N,N'-carbonyldiimidazole is reacted with a compound represented by thefollowing formula: ##STR19## wherein R¹, R⁴, and R⁶ have the samemeanings as defined above, or a salt thereof to convert the former to areactive derivative. The reactive derivative is reacted further with acompound represented by the formula: ##STR20## wherein R², R³ and##STR21## have the same meanings as defined above, or a salt thereof. Ifnecessary, any protecting groups of the amino, hydroxyl and carboxylgroup are removed by a method known per se in the art and further, thecarboxyl group is protected by a protecting group, thereby obtaining acompound represented by the formula (1) or a salt thereof. Removal ofeach protecting group can be conducted by a method known per se in theart, said method having been described in Preparation Process 1.

In the above Preparation Processes 1-3 for the compounds of the presentinvention, the target compounds (1) and (5) can each be obtained byconducting the reaction by using the sulfoxide derivative of thecorresponding cephem ring instead of the starting compound (2), (4) or(11).

Next, intermediates useful in the preparation of the compounds of thepresent invention can be prepared, for example, by the processes to bedescribed below.

a) Preparation Process A

A compound represented by the following formula: ##STR22## wherein R²,R³, R⁴, and ##STR23## have the same meanings as defined above and R⁵represents an amino or protected amino group, or a salt thereof can beprepared by reacting a compound represented by the following formula(9): ##STR24## wherein Y is a hydrogen atom, a lower alkyl group, ahalogen atom or a nitro group, said Y being optionally substituted byone to five of these groups which may be the same or different, and R⁵has the same meanings as described above or a salt thereof with acompound represented by the following formula: ##STR25## wherein R², R³and ##STR26## have the same meanings as defined above, or a salt thereofin an inert solvent and, if necessary, protecting the carboxyl group.

The reaction is conducted generally in an inert solvent such as water,methanol, ethanol, propanol, acetone, methyl ethyl ketone,tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, benzene, methylene chloride or chloroform; or ina mixed solvent of two or more of such inert solvents.

Although the reaction can be conducted generally at -78° C. to 80° C.,it is preferred to conduct it at a temperature ranging from ice coolingto room temperature. As the reaction time, it is generally sufficient toconduct the reaction for only 10 minutes to 1 hour.

Examples of the amino-protecting group represented by R⁵ are similar tothose of the amino-protecting group represented by R⁶.

The compound prepared by this process can be utilized as an intermediatefor the compound of the present invention represented by the formula (1)by removing the amino-protecting group or protecting the carboxyl groupwith a protecting group as needed. The removal of the amino-protectinggroup or the protection of the carboxyl group can be carried out by themethod known per se in the art, said method having been described inPreparation Process 1.

b) Preparation Process B

A compound represented by the following formula (7): ##STR27## whereinR⁴ and R⁵ have the same meanings as defined above is prepared byreacting a compound represented by the following formula (12): ##STR28##wherein R⁴ and R⁵ have the same meanings as defined above or a saltthereof, with phosgene or a phosgene derivative in the presence of abase. Then, the resulting compound is reacted with a compoundrepresented by the following formula: ##STR29## wherein R² and R³ havethe same meanings as defined above or a salt thereof, thereby obtaininga compound represented by the following formula (8): ##STR30## whereinR², R³, R⁴, R⁵ and ##STR31## have the same meanings as defined above.

Suitable examples of the base in the above reaction include thehydroxides or carbonates of alkali metals or alkaline earth metals, suchas sodium hydroxide, potassium hydroxide, barium hydroxide, magnesiumhydroxide, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate; tertiary amines such as triethylamine, tributylamine,N-methylmorpholine, pyridine, toluidine, lutidine, andN,N-dimethylaminopyridine.

Examples of the phosgene derivative include trichloromethylchloroformateand bis(trichloromethyl)carbonate.

The reaction is conducted generally in an inert solvent such asN,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran,dichloromethane, chloroform or ethyl acetate; or in a mixed solvent oftwo or more of such inert solvents. The reaction can be conductedgenerally at -100° C. to 30° C., but preferably at a temperature rangingfrom -78° C. to 0° C.

Compounds prepared by this process can be utilized as intermediates forthe compounds of the present invention represented by the formula (1) byremoving the amino-protecting group or protecting the carboxyl groupwith a protecting group as needed. Their removal or protection can becarried out by a method known per se in the art, said method having beendescribed in Preparation Process 1.

c) Preparation Process C

N,N'-carbonyldiimidazole is reacted with a compound represented by thefollowing formula (13) ##STR32## wherein R⁴ has the same meaning asdefined above and R⁵ a represents a protected amino group or with a saltthereof to convert the latter to an active derivative. The activederivative is reacted further with a compound represented by theformula: ##STR33## wherein R², R³ and ##STR34## have the same meaningsas defined above, or a salt thereof. If necessary, the amino group maybe deprotected, thereby obtaining a compound represented by thefollowing formula (8): ##STR35## wherein R², R³, R⁴, R⁵ and ##STR36##have the same meanings as described above.

The reaction is conducted generally in an inert solvent such as water,methanol, ethanol, propanol, acetone, methyl ethyl ketone,tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, benzene, methylene chloride or chloroform; or ina mixed solvent of two or more of such inert solvents.

Compound prepared by this process can be utilized as intermediates forthe Compounds of the present invention represented by the formula (1) byremoving any amino- and/or carboxyl-protecting group or protecting thecarboxyl group with a protecting group as needed. The deprotection canbe carried out by the method known per se in the art, said method havingbeen described in Preparation Process 1.

d) Preparation Process D

A compound represented by the following formula (14): ##STR37## whereinR², R³, R⁴ and ##STR38## have the same meanings as defined above and Xrepresents a halogen atom can be prepared by reacting the compoundrepresented by the formula (2) or a salt thereof with a compoundrepresented by the following formula:

    XCH.sub.2 COCH.sub.2 COOH

wherein X has the same meaning as defined above, or with a salt orcarboxyl-reactive derivative thereof.

Illustrative of the reactive derivative include acid halides such as theacid chloride and acid bromide. These acid halides can each be obtainedby reaction with its corresponding diketene and halogen.

The reaction is conducted generally in an inert solvent such as water,methanol, ethanol, propanol, N,N-dimethylformamide,N,N-dimethylacetamide, acetone, tetrahydrofuran, dioxane, methylenechloride, ethyl acetate, methyl acetate, acetonitrile, benzene, tolueneor pyridine; or in a mixed solvent of two or more of such inertsolvents. The reaction can be conducted generally at -78° C. to 80° C.,but preferably at a temperature ranging from ice cooling to roomtemperature.

The compound represented by the following formula (4): ##STR39## whereinR², R³, R⁴, X and ##STR40## have the same meanings as defined above or asalt thereof can be prepared by reacting a nitrosating agent with thecompound represented by the formula (14) or its salt.

Examples of the nitrosating agent include nitrous acid and itsderivatives, for example, alkali metal nitrites such as sodium nitriteand potassium nitrite; and alkyl nitrites such as butyl nitrite, pentylnitrite and amyl nitrite. When an alkali metal nitrite such as sodiumnitrite or potassium nitrite is used, it is preferred to conduct thenitrosation in the presence of an inorganic or organic acid such ashydrochloric acid, sulfuric acid, formic acid or acetic acid.

The reaction is carried out generally in an inert solvent such as water,methanol, ethanol, propanol, N,N-dimethylformamide, acetone,tetrahydrofuran, dioxane or methylene chloride; or in a mixed solvent oftwo or more of such inert solvents. The reaction can be conductedgenerally at -78° C. to 80° C., but preferably at a temperature rangingfrom ice cooling to room temperature.

e) Preparation Process E

A compound represented by the following formula (17): ##STR41## whereinR⁴ a represents a protected carboxyl group, R⁵ and Y have the samemeanings as defined above, or a salt thereof can be obtained at a highyield by reacting, in the presence of a base, a compound represented bythe following formula (15): ##STR42## wherein R⁴ a and R⁵ have the samemeanings as defined above or a salt thereof, with a compound representedby the following formula (16): ##STR43## wherein X and Y have the samemeanings as defined above.

In the next place, the carboxyl-protecting group is removed from theresulting compound, thereby obtaining the compound represented by thefollowing formula (9): ##STR44## wherein R⁵ and Y have the same meaningsas defined above or a salt thereof. Removal of calboxyl-protecting groupis carried out by the method described in Preparation Process 1.

Examples of the above-described salt of the compound represented by theformula (15) include alkali metal salts (sodium salt, potassium salt,etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.),ammonium salt, organic amine salts (trimethylamine salt, triethylaminesalt, etc.), organic acid salts (formate, trifluoroacetate,toluenesulfonate, etc.), and inorganic acid salts (hydrochloride,sulfate, etc.).

Suitable examples of the base include alkali metal salts and alkalineearth metal salts, such as sodium hydroxide, potassium hydroxide, bariumhydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate; alkali metal oralkaline earth metal salts of organic acids, such as sodium acetate,potassium acetate, barium acetate and magnesium acetate; and tertiaryamines such as triethylamine, tributylamine, N-methylmorpholine,pyridine, toluidine, lutidine, and N,N-dimethylaminopyridine.

The reaction is usually conducted in an inert solvent such asN,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dioxane,dichloromethane, chloroform, ethyl acetate, methyl acetate, benzene,toluene or hexane, or in a mixed solvent of two or more of such inertsolvents.

Although the reaction can be conducted generally at -78° C. to 80° C.,it is preferred to conduct it at a temperature ranging from ice coolingto room temperature.

In Preparation Processes A-E for intermediate compounds, the targetcompounds (4), (8) and (9) can also be obtained by using, instead of thestarting compound (9), (12), (13), (14) and (15), their sulfoxidoderivatives and then conducting reduction after the reactions.

Out of the intermediates described above, the compounds represented bythe following formula (6): ##STR45## wherein R² a and R³ a are the sameor different and individually represent a lower alkyl group, ahydroxyl-substituted lower alkyl group or a cyano-substituted loweralkyl group or the group represented by the formula ##STR46## means a4-6 membered heterocyclic group, which contains one nitrogen atom, or amorpholino group, said heterocyclic group or morpholino group beingoptionally substituted by one or more lower alkyl, hydroxyl,hydroxyl-substituted lower alkyl groups, R⁴ denotes a carboxyl group ora carboxyl group protected by a protecting group, and R⁵ represents anamino or protected amino group, the compounds represented by the formula(4) and the compounds represented by the formula (9) are all novelcompounds.

To demonstrate the efficacy of the compounds according to the presentinvention, the minimum inhibitory concentrations (MIC) of certainrepresentative compounds obtained in examples, which will follow,against various fungi and their excretion rates in urine upon oraladministration were measured, and an in vivo experiment for thetreatment of respiratory-infected model mice was conducted using suchrepresentative compounds.

a) The results of the measurement of MICs against the various fungi areshown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________           MIC (g/ml)                                                                    Staphylococcus                                                                        Escherichia                                                                         Klebsiella                                                                          Serratia                                                                            Morganella                                                                          Haemophilus                            Test   aureus  coli  pneumoniae                                                                          marcescens                                                                          morganii                                                                            influenzae                             compound                                                                             209-P   NIHJ  IID875                                                                              IID620                                                                              IID601                                                                              IID1638                                __________________________________________________________________________    Example 1                                                                            0.2     0.1   0.05  0.05  0.025 0.1                                    Example 2                                                                            0.2     0.4   0.2   0.2   0.05  0.1                                    Example 4                                                                            0.8     0.2   0.1   0.025 0.025 0.012                                  Example 6                                                                            0.8     0.2   0.2   0.025 0.012 0.012                                  Example 8                                                                            0.2     0.1   0.1   0.05  0.025 0.1                                    Example 9                                                                            0.2     0.05  0.05  0.05  0.025 0.1                                    Example 38                                                                           0.1     0.025 0.025 0.05  0.05  0.2                                    Example 39                                                                           0.2     0.05  0.025 0.05  0.05  0.2                                    Example 40                                                                           0.2     0.05  0.05  0.1   0.05  0.2                                    Example 41                                                                           0.2     0.2   0.2   0.1   0.1   0.2                                    Compound A                                                                           0.1     0.05  0.025 0.05  0.05  0.4                                    __________________________________________________________________________

Compound A in Table 1 is the following compound.

Compound A:

7-[(Z)-2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid.

As apparent from Table 1, the compounds according to the presentinvention have excellent antibacterial activities and are usefulespecially as those having strong antibacterial activities againstHaemophilus influenzae.

b) Bioavailability

Certain representative compounds according to the present invention wereeach suspended in a CMC--Na solution. The resulting suspension wasadministered orally to mice at the dosage of 20 mg/kg. Urea excretedduring 6 hours after the administration was collected. The excreteionrate in urea and bioavailability measured are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Boiavailability by oral administration                                                    Bioavailability                                                                           Recovery in urea                                      Compound    (%)         (%)                                                   ______________________________________                                        Compound B  17          11.0                                                  Compound C   7           4.5                                                  Compound D  17          10.4                                                  Example 14  38          18.2                                                  Example 20  46          22.0                                                  Example 24  34          20.0                                                  ______________________________________                                    

Compounds B, C and D in Table 2 are as follows:

Compound B:

Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate.

Compound C:

1-(Isopropyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate.

Compound D:

Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate.

c) Treatment results of respiratory-infected mice

A bacterium-containing solution was inoculated into the nasal cavity ofeach mouse, followed by the oral administration of a suspension of oneof the compounds in a CMC--Na solution one hour later where thebacterium was Haemophilus influenzae but four hours later where thebacterium was Klebsiella pneumoniae. The number of intrapulmonary viablecells of the bacterium was counted upon an elapsed time of 24 hoursafter the infection. The measurement limit is represented by thefollowing formula.

    Log CFU/Lung=1.48

wherein CFU is the colony forming unit.

When no colony was observed, the bacterium was regarded as having beeneradicated and Log CFU/Lung was calculated to be 1. The results areshown in Tables 3 and 4.

                  TABLE 3                                                         ______________________________________                                        Klebsiella pneumoniae E02033,                                                 Inoculum size: 1.4 × 10.sup.3 CFU/mouse                                                            Intrapulmonary                                                                          Eradi-                                            MIC      Dosage   viable cells                                                                            cation                                   Compound (μg/ml)                                                                             (mg/kg)  (log CFU/lung)                                                                          rate (%)                                 ______________________________________                                        Example 20                                                                             0.1      10       1.66 ± 1.02                                                                          50                                       Compound E                                                                             0.2      10       4.26 ± 0.62                                                                          0                                        Compound F                                                                             0.2      10       6.25 ± 0.74                                                                          0                                        Control  --       --       7.31 ± 0.73                                                                          0                                        ______________________________________                                    

Compounds E and F in Table 3 are as follows:

Compound E:

1-(Isopropyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.

Compound F:

7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid.

                  TABLE 4                                                         ______________________________________                                        Haemophilus influenzae E35147,                                                Inocolum size: 4.3 × 10.sup.5 CFU/mouse                                                                Intrapulmonary                                            MIC        Dosage   viable cells                                   Compound   (μg/ml) (mg/kg)  (Log CFU/Lung)                                 ______________________________________                                        Example 20 0.1        40       3.51 ± 0.37                                 Example 43 0.2        40       4.86 ± 0.60                                 Compound C 0.8        40       5.50 ± 0.61                                 Compound F 0.8        40       5.16 ± 0.73                                 Control    --         --       5.73 ± 0.58                                 ______________________________________                                    

Compound C in Table 4 is the same as that in Table 2 and Compound F inTable 4 is the same as that in Table 3.

As is envisaged from the above tables, the compounds according to thepresent invention have properties as excellent orally antibacterialagents.

The acute toxicity, LD₅₀ (mouse, p.o.), of the compounds according tothe present invention were all 2 g/kg or greater.

To use the compounds of the present invention as antibacterialcompositions, they can be administered orally or parenterally in 1-4portions at a total daily dosage of 100 mg to 5 g in general. The dosagevaries depending on the age and conditions.

Dosable preparation forms include tablets, granules, powders, capsules,syrups, liquids, etc. Each of these preparations can be formulated in amanner known per se in the art, by adding a known excipient.

Examples will next be set out to describe the present invention infurther detail. It is, however, to be noted that the present inventionis not limited by the following examples.

Starting materials employed upon preparation of the compounds of thepresent invention will be described as preparation examples.

Throughout the examples, "Tr" stands for a (C₆ H₅)₃ C-- group, "BH" fora (C₆ H₅)₂ CH-- group, and Me for a methyl group.

Preparation Example 1

Benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR47##

A solution of benzhydryl7-thienylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (30 g; 0.058mol) in tetrahydrofuran (600 ml) was stirred under ice cooling, to whichN,N'-carbonyldiimidazole (11.25 g; 0.069 mol) was added, followed bystirring under ice cooling for further three hours. The reaction mixturewas added with ethyl acetate (1 l), and the resulting mixture was washedwith water (400 ml). The organic layer was stirred under ice cooling,followed by the addition of a 50% aqueous dimethylamine solution (12 g;0.075 mol). They were reacted for one hour. The reaction mixture wasdried over anhydrous magnesium sulfate and then concentrated, whereby amixture of benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylateand benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-2-cephem-4-carboxylatewas obtained (24 g).

To a solution of the resulting mixture in tetrahydrofuran (400 ml), asolution of m-chloroperbenzoic acid (20 g; 0.116 mol) in tetrahydrofuran(100 ml) was added in portions, followed by stirring for one and a halfhours under ice cooling. The reaction mixture was concentrated underreduced pressure and the residue was washed with ether. After furtherconcentration under reduced pressure, the residue was purified bychromatography on a silica gel column, whereby the title compound wasobtained (7.5 g; yield: 21%).

NMR (CDCl₃, δ): 2.84(3H,s), 2.92(3H,s), 3.23,3.88(2H,ABq,J=18 Hz),3.88(2H,s), 4.48(2H,d,J=4 Hz), 4.78,5.34 (2H,ABq, J=8 Hz),6.15(1H,dd,J=4 Hz,8 Hz), 6.90-7.10(2H,m), 6.97(1H,s), 7.2-7.6(11H,m)

Preparation Example 2

Benzhydryl7-thienylacetamido-3-N,N-dimethyl-carbamoyloxymethyl-3-cephem-4-carboxylat##STR48##

A solution of benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide(5 g; 8.2 mmol), which had been obtained in Preparation Example 1, inN,N-dimethylformamide (50 ml) was stirred under ice cooling, followed bythe addition of phosphorus trichloride (2.5 g; 18 mmol). The resultingsolution was stirred for 30 minutes and added with ethyl acetate (500ml). The resulting mixture was washed with water and a saturated aqueoussodium chloride solution and thereafter added with anhydrous magnesiumsulfate. After the organic layer was concentrated under reducedpressure, the residue was solidified from a mixed solvent of acetone andisopropyl ether. The resulting solid was collected by filtration,whereby the title compound was obtained (3.8 g; yield: 79%).

NMR (CDCl₃, δ): 2.82(3H,s), 2.90(3H,s), 3.40,3.55(2H,ABq,J=18 Hz),3.84(2H,s), 4.81,5.06(2H,ABq,J=12 Hz), 4.98 (1H,d, J=4 Hz),5.84(1H,dd,J=4 Hz,8 Hz), 6.27(1H,d,J=8 Hz), 6.94(1H,s), 6.98-7.02(2H,m),7.25-7.43(11H,m)

Preparation Example 3

Benzhydryl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatehydrochloride ##STR49##

A solution of phosphorus pentachloride (2.8 g; 13 mmol) and pyridine(1.04 g; 13 mmol) in methylene chloride (80 ml) was cooled to -10° C. Tothe resulting solution, benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(1.6 g; 2.7 mmol), which had been obtained in Preparation Example 2, wasadded, followed by stirring at -10° C. for one hour. The resultingsolution was cooled down to -20° C. and then added with 1,3-propanediol(1 ml). They were stirred at -20° C. for one hour. The reaction mixturewas added with methanol (10 ml), and the resulting mixture was heated tothe room temperature and thereafter washed with water (50 ml) added. Theorganic layer was dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was solidified withether and isopropyl ether, whereby the title compound was obtained (1.0g; yield: 74%).

NMR (CDCl₃, δ): 2.83(3H,s), 2.90(3H,s), 3.43,3.58(2H,ABq,J=18 Hz),4.80,5.06(2H,ABq,J=12 Hz), 4.8(1H,m), 4.97(1H,d, J=4 Hz), 6.98(1H,s),7.25-7.50(10H,m)

Ethyl acetate was dissolved in the hydrochloride (1.0 g) which had beenobtained in the above step. The resulting solution was added with anaqueous solution of sodium hydrocarbonate to neutralize the solution.The organic layer was washed with water and then with a saturatedaqueous sodium chloride solution, followed by drying over anhydrousmagnesium sulfate and concentration under reduced pressure, wherebybenzhydryl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (0.9 g)was obtained.

Preparation Example 4

Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR50##

A solution of (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoaceticacid (1.9 g; 2.8 mmol), 1-hydroxy-1H-benztriazole (0.4 g; 2.9 mmol) anddicyclohexylcarbodiimide (0.6 g; 2.9 mmol) in dimethylformamide (20 ml)was stirred at room temperature for 30 minutes. To the resultingsolution, benzhydryl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (1.3 g;2.8 mmol), which had been obtained in the second step of PreparationExample 3, was added, followed by stirring for 3 hours. The reactionmixture was added with ethyl acetate (300 ml) and the resulting mixturewas washed with water and a saturated aqueous sodium chloride solution,followed by drying over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the concentrate was subjected to chromatographyon a silica gel column, whereby the title compound was obtained (1.4 g;yield: 45%).

NMR (CDCl₃, δ): 2.82(3H,s), 2.91(3H,s), 3.36,3.48(2H,ABq,J=18 Hz),4.81,5.14(2H,ABq,J=12 Hz), 5.05(1H,d,J=4 Hz), 6.08(1H,dd,J=4 Hz,8 Hz),6.43(1H,s), 6.80(1H,s), 6.97(1H,s), 7.18-7.50(42H,m)

Preparation Example 5

Benzhydryl7-thienylacetamido-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR51##

In a similar manner to Preparation Example 1, the title compound wasobtained (yield: 9%).

NMR (CDCl₃, δ): 1.0-1.18(3H,m), 3.80(3/2H,s), 3.86(3/2H,s),3.18-3.5(3H,m), 3.80-3.90(2H,m), 3.85(2H,s), 4.44-4.46(1H,m),4.74(1H,d,J=13 Hz), 5.24-5.38(1H,m), 6.07(1H,dd,J=5 Hz,8 Hz),6.9-7.02(4H,m), 7.23-7.50(11H,m)

Preparation Example 6

Benzhydryl7-thienylacetamido-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR52##

In a similar manner to Preparation Example 2, the title compound wasobtained (yield: 66%).

NMR (CDCl₃, δ):

1.0-1.15(3H,m), 2.8(3/2H,s), 2.87(3/2H,s), 3.18-3.35(2H,m),3.40-3.55(2H,ABq,J=18 Hz), 3.86(2H,s), 4.8(1H,d,J=14 Hz), 4.97(1H,d,J=5Hz), 5.05-5.15 (1H,m), 5.87(1H,dd,J=5 Hz,8 Hz), 6.28(1H,d,J=8 Hz),6.93(1H,s), 6.95-7.02(2H,m), 7.2-7.5(11H,m)

Preparation Example 7

Benzhydryl 7-amino-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate hydrochloride ##STR53##

In a similar manner to Preparation Example 3, the title compound wasobtained (yield: 81%).

NMR (CDCl₃, δ): 1.0-1.15(3H,m), 2.78(3/2H,s), 2.85(3/2H,s),3.1-3.35(2H,m), 3.40-3.62(2H,ABq,J=18 Hz), 4.87(1H,d, J=12 Hz),4.92(1H,d,^(J=) 5 Hz), 4.98(1H,m), 5.17-5.23(1H,m), 6.93(1H,s),7.15-7.40(10H,m)

Preparation Example 8

Benzhydryl7-[2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR54##

In a similar manner to Preparation Example 4, the title compound wasobtained (yield: 72%).

NMR (CDCl₃, δ):

1.1-1.2(3H,m), 2.79(3/2H,s), 2.87(3/2H,s), 3.18-3.35(3H,m),3.48(1H,d,J=18 Hz), 4.82(1H,d,J=12 Hz), 5.06(1H,d,J=5 Hz), 5.07-5.15(1H,m), 6.07(1H,dd, J=5 Hz,8 Hz), 6.43(1H,s), 6.83(1H,s), 6.95 (1H, s),7.1-7.4(40H,m), 7.47(1H,d,J=8 Hz)

Preparation Example 9

Benzhydryl7-thienylacetamido-3-(1morpholinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR55##

In a similar manner to Preparation Example 1, the title compound wasobtained (yield: 53%).

NMR (DMSO-d₆, δ) 3.3-3.4(4H,m), 3.5-3.6(4H,m), 3.64,4.03(2H, ABq,J=19Hz), 4.62,5.17(2H,ABq,J=12 Hz), 4.95-5.00(1H,m), 5.95-6.00(1H,m),6.98-7.05(3H,m), 7.1-7.6(11H,m), 8.47(1H,d,J=8 Hz)

Preparation Example 10

Benzhydryl7-thienylacetamido-3-(1-morpholinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR56##

In a similar manner to Preparation Example 2, the title compound wasobtained (yield: 52%).

NMR (CDCl₃, δ): 3.3-3.5(4H,m), 3.55-3.70(4H,m), 3.40,3.58(2H, ABq,J=19Hz), 3.87(2H,s), 4.82,5.09(2H,ABq,J=13 Hz), 4.97(1H,d,J=5 Hz),5.87(1H,d,J=5 Hz,8 Hz), 6.25(1H,d,J=8 Hz), 6.94(1H,s), 6.95-7.05(2H,m),7.25-7.45(11H,m)

Preparation Example 11

Benzhydryl7-amino-3-(1-morpholinyl)carbonyloxymethyl-3-cephem-4-carboxylatehydrochloride ##STR57##

In a similar manner to Preparation Example 3, the title compound wasobtained (yield: 62%).

NMR (CDCl₃, δ): 3.3-3.5(5H,m), 3.5-3.8(5H,m), 4.98,5.24(2H, ABq,J=12Hz), 5.0-5.1(1H,m), 5.14-5.17(1H,m), 6.94(1H,s), 7.2-7.5(10H,m)

Preparation Example 12

Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-morpholinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR58##

In a similar manner to Preparation Example 4, the title compound wasobtained (yield: 59%).

NMR (CDCl₃, δ): 3.26,3.50(2H,ABq,J=19 Hz), 3.3-3.7(8H,m),4.82,5.11(2H,ABq,J=13 Hz), 5.05(1H,d,J=5 Hz), 6.2(1H,dd,J=5 Hz,8 Hz),6.44(1H,s), 6.85(1H,br.s), 6.96 (1H,s), 7.15-7.5(41H,m)

Preparation Example 13

Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR59##

To a solution of phosphorus pentachloride (3.4 g) and pyridine (1.3 g)in dichloromethane (100 ml), a solution of benzhydryl7-thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(2 g) in N,N-dimethylformamide (6 ml) and dichloromethane (100 ml) wasadded under ice cooling and the resulting solution was stirred at thesame temperature for 30 minutes. The reaction mixture was then addedwith 1,3-butanediol (4 ml) under cooling in a dry ice-methanol bath(-50° C.), followed by stirring at the same temperature for 50 minutes.After methanol (4 ml) was added to the reaction mixture at the sametemperature, the dry ice-methanol bath was removed and the mixture wasallowed to stand until its temperature returned to room temperature. Thereaction mixture was added with water and dichloromethane, followed bycollection of the dichloromethane layer and then, by further extractionof the water layer with dichloromethane. Both dichloromethane layerswere combined together and were washed successively with Water and asaturated aqueous sodium chloride solution, followed by drying overmagnesium sulfate. The solvent was then distilled off under reducedpressure. The residue was dissolved in ethyl acetate and the resultingsolution was washed with a dilute aqueous solution of sodiumhydrogencarbonate (containing 1.1 equivalent of sodium hydrogencarbonatebased on the raw material), followed by drying over magnesium sulfate.Then, the solvent was distilled off under reduced pressure. The residuewas dissolved in N,N-dimethylformamide (15 ml). To the resultingsolution, (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid(1.53 g), 1-hydroxy-1H-benztriazole (0.55 g) anddicyclohexylcarbodiimide (0.78 g) were added, followed by stirring atroom temperature for 2 hours and 40 minutes. The reaction mixture wasadded with ethyl acetate and water. After the collection of the ethylacetate layer, the water layer was extracted further with ethyl acetate.Both ethyl acetate layers were combined together, washed successivelywith water and a saturated aqueous sodium chloride solution, and driedover magnesium sulfate. Then, the solvent was distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column, whereby benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (1.46 g, 48.2%).

NMR (CDCl₃, δ): 2.83(3H,s), 2.89(3H,s), 3.36-3.50(2H,ABq,J=18.8 Hz),4.04(3H,s), 4.84,5.10(2H,ABq,J=13.7 Hz), 5.04(1H,d, J=4.9 Hz), 5.92-5.96(1H,m), 6.76(1H,s), 6.94(1H,s), 7.20-7.45(25H,m)

Preparation Example 14

Benzhydryl7-[(Z)-2-(5-tritylamino-1,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3-(N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR60##

In a similar manner to Preparation Example 13, the title compound wasobtained (yield: 71%).

NMR (CD₃ OD, δ): 2.65-2.87(6H,m), 3.47,3.72(2H,ABq,J=18.5 Hz),4.07(3H,s), 5.18(1H,d,J=5.1 Hz), 5.94(1H,d, J=5.1 Hz), 6.93(1H,s),7.25-7.45(25H,m)

Preparation Example 15

Benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-monofluoromethoxyiminoacetamido]-3-(N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate ##STR61##

In a similar manner to Preparation Example 13, the title compound wasobtained (yield: 64%).

NMR (CDCl₃, δ): 2.82(3H,s), 2.86(3H,s), 3.43,3.56(2H,ABq,J=18.7 Hz),4.82,5.09(2H,ABq,J=13.9 Hz), 5.05(1H,d,J=4.9 Hz),5.72,5.86(2H,ABq,d,J=3.6 Hz,55 Hz), 5.94(1H,dd, J=4.9 Hz,8.4 Hz),6.81(1H,s), 6.93(1H,s), 7.03(1H,d,J=8.4 Hz),7.28-7.45(25H,m)

PREPARATION EXAMPLE 16 Benzhydryl7-formamido-3-(1-piperidinyl)carbonyloxymethyl-2-cephem-4-carboxylate##STR62##

To a solution of benzhydryl 7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate (4.24 g) in tetrahydrofuran (80 ml),N,N'-carbonyldiimidazole (1.62 g) was added under ice cooling, followedby stirring at the same temperature for 1 hour and 25 minutes. Then, theresulting solution was added with a solution of piperidine (0.85 g) intetrahydrofuran (10 ml) and stirred at the same temperature for 1 hourand 20 minutes. Further stirring was conducted for one hour at roomtemperature. The reaction mixture was added with piperidine (0.17 g),followed by stirring at room temperature for 11 hours and 10 minutes andthen, the

resulting reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate. The resulting solution waswashed successively with 1N hydrochloric acid, water and a saturatedaqueous chloride solution, followed by drying over magnesium sulfate.Then, the solvent was distilled off under reduced pressure. The residuewas purified by chromatography on a silica gel column, wherebybenzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-2-cephera-4-carboxylate (2.3 g, 43.0%).

NMR (CDCl₃, δ):

1.20-1.40(6H,m), 3.30-3.40(4H,m), 4.57,4.66(2H, ABq,J=12.8 Hz),5.13(1H,s), 5.22(1H,d,J=4.0 Hz), 5.70-5.75(1H,m), 6.44(1H,s),6.89(1H,s), 7.25-7.40(10H,m), 8.23(1H,s)

PREPARATION EXAMPLE 17 Benzhydryl7-formamido-3-(1-piperidinyl)carbonyloxymethy-1-3-cephem-4-carboxylate-1-oxide##STR63##

To a solution of benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-2-cephem-4-carboxylate (3.4 g) in ethyl acetate (20ml), m-chloroperbenzoic acid (1.53 g) was added under ice cooling,followed by stirring at the same temperature for 55 minutes. To thereaction mixture, m-chloroperbenzoic acid (0.15 g) was added, followedby stirring under ice cooling for 35 minutes. The crystals precipitatedwere collected by filtration. The filtrate was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column, whereby benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxyethyl -3-cephem-4-carboxylate-1-oxide (1.53 g, 43.7%) wasobtained together with precipitated crystals.

NMR (DMSO-d₆, δ):

1.35-1.55(6H,m), 3.23-3.30(4H,m), 3.65,4.01(2H,ABq, J=18.7 Hz),4.58,5.11(2H,ABq,J=13.6 Hz), 4.98(1H, d,J=3.7 Hz), 6.05(1H,m),6.93(1H,s), 7.25-7.55(10H,m), 8.15(1H,s), 8.43(1H,d,J=9.5 Hz)

PREPARATION EXAMPLE 18 Benzhydryl7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR64##

To a solution of benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1oxide (2.07 g) inN,N-dimethylformamide (25 ml), phosphorus trichloride (1 ml) was addedunder cooling in a dry ice-ethanol bath (-60° C.), followed by stirringfor 35 minutes. The reaction mixture was successively added with ethylacetate and water under cooling in a dry ice-ethanol bath and then, theresulting mixture was increased to room temperature. The ethyl acetatelayer was collected and the water layer was extracted further with ethylacetate. Both ethyl acetate layers were combined together, successivelywashed with water and a saturated aqueous sodium chloride solution, andthen dried over magnesium sulfate. Then, the solvent was distilled offunder reduced pressure. The residue was purified by chromatography on asilica gel column, whereby benzhydryl7-formamido-3-(1-piperidinyl)carbonyloxymethyl -3-cephem-4-carboxylate(1.87 g, 93.0%) was obtained.

NMR (CDCl₃, δ):

1.35-1.55(6H,m), 3.20-3.35(4H,m), 3.35,3.46(2H, ABq,J=18.7 Hz),4.76,5.03 (2H,ABq,J=13.9 Hz), 4.90(1H,d,J=3.5 Hz), 5.80-5.85(1H,m),6.86(1H,s), 7.14-7.40(10H,m), 7.84(1H,d,J=9.2 Hz), 8.15(1H,s)

PREPARATION EXAMPLE 19 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR65##

To a solution of benzhydryl 7-formamido-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.87 g) intetrahydrofuran-methanol (1:1, 20 ml), 36% hydrochloric acid (2 ml) wasadded and the resulting solution was stirred at room temperature for 2hours and 10 minutes. Then, the solvent was distilled off under reducedpressure. The residue was added with ethyl acetate and water. The ethylacetate layer was collected and the water layer was extracted furtherwith ethyl acetate. Both ethyl acetate layers were combined together,washed with a saturated aqueous sodium chloride solution and then, driedover magnesium sulfate. The solvent was thereafter distilled off underreduced pressure. The residue was dissolved in N,N-dimethylformamide (18ml). To the resulting solution,(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (2.35 g),1-hydroxy-1H-benztriazole (0.56 g) and dicyclohexylcarbodiimide (0.79 g)were added, followed by stirring at room temperature for 1 hour and 5minutes. The reaction mixture was added with ethyl acetate and water.The ethyl acetate layer was collected and the water layer was extractedfurther with ethyl acetate. Both ethyl acetate layers were combinedtogether, washed successively with water and a saturated aqueous sodiumchloride solution and then was dried over magnesium sulfate. The solventwas thereafter distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column, whereby benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate (1.4 g, 33.7%).

NMR (CDCl₃,δ):

1.42-1.64(6H,m), 3.25-3.43(4H,m), 3.26,3.48 (2H,ABq,J=18.6 Hz),4.82,5.12(2H,ABq,J=13.9 Hz), 5.05(1H,d,J=4.9 Hz), 6.05-6.12(1H,m),6.44(1H,s), 6.96(1H,s), 7.15-7.43(40H,m)

PREPARATION EXAMPLE 20

Benzhydryl7-formamido-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR66##

In a similar manner to Preparation Example 16, the title compound wasobtained (yield: 58%).

NMR (CDCl₃, δ):

2.15-2.25(2H,m), 3.90-4.00(4H,m), 4.55,4.61 (2H,ABq,J=12.7 Hz),5.13(1H,s), 5.21 (1H,d,J=4.0 Hz), 5.69(1H,dd,J=4.0 Hz,9.2 Hz),6.44(1H,s), 6.82(1H,d, J=9.2 Hz), 6.90(1H,s), 7.28-7.40(10H,m),8.22(1H,s)

PREPARATION EXAMPLE 21 Benzhydryl7-formamido-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR67##

In a similar manner to Preparation Example 17, the title compound wasobtained (yield: 44%).

NMR (CDCl₃, δ):

2.15-2.25 (2H,m), 3.20,3.82 (2H,ABq,J=18.9 Hz), 3.90-4.05(4H,m),4.45(1H,d,J=4.8 Hz) ) 4.72,5.24 (2H,ABq,J=14.3 Hz), 6.07(1H,m),6.93(1H,s), 7.20-7.50(10H,m), 8.21(1H,s)

PREPARATION EXAMPLE 22 Benzhydryl7-formamido-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR68##

In a similar manner to Preparation Example 18, the title compound wasobtained (yield: 97%).

NMR (CDCl₃, δ):

2.15-2.25(2H,m), 3.44,3.57(2H,ABq,J=18.7 Hz), 3.85-4.10 (4H,m),4.83,5.06 (2H,ABq,J=13.9 Hz), 4.99(1H,d,J=4.9 Hz), 5.93(1H,dd,J=4.9Hz,9.2 Hz), 6.39(1H,d,J=9.21 Hz), 6.95(1H,s), 7.25-7.45(10H,m),8.25(1H,s)

PREPARATION EXAMPLE 23 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR69##

In a similar manner to Preparation Example 19, the title compound wasobtained (yield: 94%).

NMR (CDCl₃, δ):

2.15-2.27 (2H,m), 3.26,3.50(2H,ABq,J=18.5 Hz), 3.85-4.10(4H,m),4.82,5.08(2H,ABq,J=13.8 Hz), 5.05(1H,d,J=4.9 Hz), 6.11(1H,dd,J=4.9Hz,8.8 Hz), 6.47(1H,s), 6.99(1H,s), 7.15-7.53(40H,m)

PREPARATION EXAMPLE 24

Mixture of benzhydryl 7-formamido-3-[N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl]-2-cephem-4-carboxylate and benzhydryl7-formamido-3-[N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl]-2-cephem-4-carboxylate ##STR70##

In a similar manner to Preparation Example 16, the title compound wasobtained (yield: 51%).

NMR (CDCl₃, δ):

2.90-2.97(3H,m), 3.24-3.35(2H,m), 3.49,3.59(10/12H, ABq,J=19 Hz),3.61-3.70(2H,m), 4.57-4.76(14/12H,m), 4.86-4.90,5.09-5.18(10/12H,m),4.99(5/12H,d,J=5 Hz), 5.18(7/12H,s), 5.24(7/12H,d,J=5 Hz), 5.65-5.68(7/12H,m), 5.93(5/12H,dd,J=5 Hz,9 Hz), 6.47-6.50 (7/12H,m),6.91(7/12H,s), 6.99(5/12H,s), 7.15-7.20 (10H,m), 8.22(1H,s)

PREPARATION EXAMPLE 25 Benzhydryl7-formamido-3-(N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR71##

In a similar manner to Preparation Example 17, the title compound wasobtained (yield: 49%).

NMR (CDCl₃, δ):

2.87(3/2H, s), 2.90(3/2H,s), 3.22-3.29(1H,m),3.36-3.41(1H,m),3.59-3.62(1H,m), 3.69,3.71(1H,m), 3.94,4.09(2H,ABq,J=20 Hz),4.46-4.56(1H,m), 4.77-4.81(1H,m), 5.23-5.29(1H,m), 6.08-6.10(1H,m),6.94(1H,s), 8.22(1H,s)

PREPARATION EXAMPLE 26 Benzhydryl7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl]-3-cephem-4-carboxylate##STR72##

In a similar manner to Preparation Example 19, the title compound wasobtained (yield: 12%).

NMR (CDCl₃, δ):

2.94-2.97 (3H,m), 3.24-3.30(3H,m), 3.43-3.52(3H,m), 4.80-4.83 (1H,m),5.06 (1H, d, J=5 Hz), 5.10-5.15 (1H,m), 6.11 (1H,dd,J=5 Hz, 9 Hz),6.44(1H,s), 6.96(1H,s), 7.2-7.4 (40H,m)

PREPARATION EXAMPLE 27 Benzhydryl7-formamido-3-N-carbamoylmethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR73##

To a solution mixture of benzhydryl 7-formamido-3-(1-imidazoryl)carbonyl oxymethyl-2-cephem-4-carboxylate-1-oxide (5.4 g) in atetrahydrofuran (90 ml), and water (18 ml) mixture, sarcosinamidehydrochloride (1.9 g) and pyridine (1.23 ml) were added, followed bystirring at room temperature for 15 hours and at 45° C. for 12 hours.After the reaction mixture was concentrated, the residue was added withwater and ethyl acetate. The ethyl acetate layer was successively washedwith 1N hydrochloric acid, water and a saturated aqueous sodium chloridesolution, dried over magnesium sulfate and then concentrated. Theresidue was purified by chromatography on a silica gel column, wherebythe title compound was obtained (yield: 750 mg; 15.0%)

NMR (CDCl₃, δ):

2.78(3H,m), 3.78(2H,m), 3.5-4.1(2H,m)., 4.95(1H,m), 4.5-5.1(2H,m),6.03(1H,m), 6.9(1H,m), 7.2-7.5(10H,m), 8.14(1H,s), 8.42(1H,d,J=8 Hz)

PREPARATION EXAMPLE 28 Benzhydryl7-formamido-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR74##

In a similar manner to Preparation Example 18, the title compound wasobtained (yield: 66%).

NMR (CDCl₃, δ):

2.94(3H,S), 3.4-4.3(4H,m), 4.87,5.15(2H,ABq,J=18 Hz), 5.08(1H,d,J=4 Hz),5.96(1H,dd,J=4 Hz,8 Hz), 6.45(1H,br.s), 6.94(1H,s), 7.2-7.45(10H,m),8.26(1H,s)

PREPARATION EXAMPLE 29 Benzhyhydryl7-[(Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR75##

To a solution of benzhydryl7-formamido-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (430 mg) in a methanol (6 ml), andtetrahydrofuran (6 ml) mixture, concentrated hydrochloric acid (0.8 ml)was added dropwise under ice cooling, followed by stirring at roomtemperature for 2 hours. The reaction mixture was concentrated, addedwith ethyl acetate, successively washed with water, a saturated aqueoussolution of sodium bicarbonate and a saturated aqueous sodium chloridesolution, dried over magnesium sulfate and then concentrated.

To a solution of the residue thus obtained (410 mg) inN,N-dimethylformamide (8 ml), (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (610 mg), dicyclohexylcarbodiimide (197 mg)and 1-hydroxybenzotriazole (123 mg) were added, followed by stirring atroom temperature for 10 hours. The reaction mixture was added with waterand ethyl acetate. The ethyl acetate layer was successively washed withwater, 1N hydrochloric acid, a saturated aqueous solution of sodiumbicarbonate and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate and then concentrated. The residue was purified bychromatography on a silica gel column, whereby the title compound wasobtained (yield: 460 mg; 44.5 %).

NMR (CDCl₃, δ):

2.87 (0.6H,br.s), 2.96(0.4H,br.s), 3.08-3.48(2H,m), 3.8-4.3(2H,m),4.7-5.2(2H,m), 5.04(1H,d,J=5 Hz), 6.10(1H,dd,J=5 Hz,8 Hz), 6.45(1H,s),6.96(1H,s), 7.1-7.5 (40H,m)

PREPARATION EXAMPLE 30 Benzhydryl7-formamido-3-(3-hydroxy-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate and 2-cephem derivative thereof##STR76##

In a similar manner to Preparation Example 16, the title compound wasobtained (yield: 28%).

NMR (CDCl₃, δ):

1.9(2H,m), 3.2-3.6(4H,m), 4.4-4.8(3H,m), 5.01(0.3H,d,J=5 Hz),5.17(0.7H,s), 5.23(0.7H,s), 5.70 (0.7H,m), 5.94(0.3H,m), 6.48(1H,m),6.91(0.7H,s), 6.95(0.3H,s), 7.25-7.45(10H,m), 8.25(1H,m)

PREPARATION EXAMPLE 31 Benzhydryl7-formamido-3-(3-hydroxy-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide ##STR77##

In a similar manner to Preparation Example 17, the title compound wasobtained (yield: 68%).

NMR (DMSO-d₆, δ):

1.6-1.95(2H,m), 3.1-3.4(4H,m), 3.84(2H,m), 4.86(2H,m), 4.98(2H,m),6.05(1H,dd,J=9.8 Hz,5 Hz), 6.93(1H,s), 7.24-7.53(10H,m), 8.15(1H,s),8.42(1H,d,J=9.8 Hz)

PREPARATION EXAMPLE 32 Benzhydryl7-formamido-3-(3-hydroxy-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR78##

In a similar manner to Preparation Example 18, the title compound wasobtained (yield: 78%).

NMR (CDCl₃, δ):

2.16(2H,m), 3.3-3.7(6H,m), 4.99(1H,d,J=5 Hz), 4.8-5.2 (2H,m),5.48(1H,br.s), 5.93 (1H, dd, J=9 Hz, 5 Hz ) 6.48(1H,d,J=9 Hz),6.95(1H,s), 7.2-7.4 (1H,s), 8.24 (1H, s)

PREPARATION EXAMPLE 33 Benzhydryl7-[(Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-hydroxy-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR79##

In a similar manner to preparation Example 19, the title compound wasobtained (yield: 6%).

NMR (CDCl₃, δ):

1.97 (2H,m), 3.1-3.5(6H,m), 4.26(1H,b), 4.98(1H,d,J=5 Hz),4.7-5.2(2H,m), 6.05(1H,dd, J=9 Hz,5 Hz), 6.46(1H,s), 6.94(1H,s),7.1-7.5(40H,m)

PREPARATION EXAMPLE 34 Benzhydryl7-formamido-3-[((S)-(+)-2-hydroxymethyl-1-pyrrolidinyl)carbonyloxymethyl]-3-cephem-4-carboxylate and 2-cephem derivativethereof ##STR80##

In a similar manner to preparation Example 16, the title compound wasobtained (yield: 16%).

NMR (CDCl₃, δ):

1.7-2.1(4H,m), 3.2-4.0(4.4H,m), 4.65(1H,m), 4.6-5.3(1.2H,m),4.86,5.15(0-8H,ABq,J=14 Hz) 5.01(0.4H,d,J=5 Hz), 5.18(0.6H,s),5.25(0.6H,m), 5.72(0.6H,m), 5.94(0.4H,dd,J=9 Hz,5 Hz), 6.45(0.6H,m),6.91(1H,s), 7.2-7.5(10H,m), 8.25(1H,s)

PREPARATION EXAMPLE 35 Benzhydryl7-formamido-3-[((S)-(+)-2-hydroxymethyl-1-pyrrolidinyl)carbonyloxymethyl]-3-cephem-4-carboxylate-1-oxide ##STR81##

In a similar manner to Preparation Example 17, the title compound wasobtained (yield: 59%).

NMR (CDCl₃, δ):

1.5-2.1(4H,m), 3.2-4.0(6H,m), 4.53(1H,m), 4.80,5.34(2H,ABq,J=14 Hz),5.25(1H,m), 6.15(1H,dd, J=9 Hz,15 Hz), 7.97 (1H,s), 7.2-7.5(10H,m), 8.27(1H,s)

PREPARATION EXAMPLE 36 Benzhydryl7-formamido-3-[((S)-(+)-2-hydroxymethyl-1-pyrrolidinyl)carbonyloxymethyl]-3-cephem-4-carboxylate ##STR82##

In a similar manner to Preparation Example 18, the title compound wasobtained (yield: 74%).

NMR (CDCl₃, δ):

1.80-2.10(4H,m), 3.27-3.56(6H,m), 3.90(1H,m), 4.97 (1H,d,J=4.8 Hz),5.01(2H,ABq,J=14 Hz), 5.90(1H,dd,J=4.8 Hz,8.9 Hz), 6.94(1H,s),7.23-7.44(10H,m), 8.18(1H,s)

PREPARATION EXAMPLE 37 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(S)-(+)-2-hydroxymethylpyrrolidino]carbonyloxymethyl-3-cephem-4-carboxylate##STR83##

In a similar manner to Preparation Example 19, the title compound wasobtained (yield: 6%).

NMR (CDCl₃, δ):

1.80-2.00(4H,m), 3.21-3.60(6H,m), 3.90(1H,m), 5.02(1H,d,J=4.8 Hz),5.08(2H,ABq,J=14 Hz), 6.07 (1H,dd,J=4.8 Hz,8.8 Hz), 6.45(1H,s),6.95(1H,s), 7.20-7.40(40H,m)

PREPARATION EXAMPLE 38

Mixture of benzhydryl7-[(Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-pyrrolidinyl) carbonyloxymethyl-3-cephem-4-carboxylateand benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-pyrrolidinyl) carbonyloxymethyl-2-cephem-4-carboxylate##STR84##

In tetrahydrofuran (200 ml), 2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (20 g), 1-hydroxybenzotriazole (6 g) anddicyclohexylcarbodiimide (9.2 g) were dissolved. The resulting solutionwas stirred at room temperature for 1 hour and 15 minutes (Liquid A).

On the other hand, 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid(10.3 g) was suspended in acetonitrile (500 ml), followed by theaddition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (24.8 ml) atroom temperature. The resulting suspension was stirred at roomtemperature for 20 minutes (Liquid B).

After filtration of Liquid A, the solvent was distilled off underreduced pressure. The residue thus obtained was recrystallized from amixed solvent of n-hexane and isopropyl ether so that powdery crystalswere formed. They were dissolved in tetrahydrofuran (50 ml) and theresulting solution was added to Liquid B at room temperature, followedby stirring for one hour and 15 minutes.

The reaction mixture was thereafter filtered and the filtrate was addedwith diphenyldiazomethane (11.6 g) and methanol (8.6 g), followed bystirring at room temperature for 2 hours. The reaction mixture wasdistilled off under reduced pressure. The residue thus obtained wasdissolved in tetrahydrofuran (120 ml) and the resulting solution wasadded with N,N'-carbonyldiimizazole (4.9 g) at room temperature,followed by stirring at the same temperature for 2 hours.

In the next place, the reaction mixture was added with pyrrolidine (3.49g), followed by stirring for 2 hours and 20 minutes. The reactionmixture was distilled off under reduced pressure. The residue thusobtained was purified by column chromatography (SiO₂ 250 g;benzene:ethyl acetate=8:1), whereby the title compound was obtained(yield: 6.94 g; 20%).

NMR (CDCl₃, δ):

1.80-1.95(4H,m), 3.25-3.30(4H,m), 4.60(6/5H,s), 4.82,5.10(2H,ABq,J=13Hz), 5.05(2/5H,d,J=5 Hz), 5.18(3/5H,s), 5.25(3/5H,d,J=5 Hz),5.85(3/5H,dd, J=5 Hz,9 Hz), 6.15(2/5H,dd,J=5 Hz,9 Hz), 6.22(3/5H,s),6.42(3/5H,s), 6.44(2/5H,s), 7.01,7.03(1H,s), 7.25-7.40 (40H,m)

PREPARATION EXAMPLE 39 Benzhydryl7-[(Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide ##STR85##

To a solution of the mixture (3.7 g), which had been obtained inPreparation Example 38, in tetrahydrofuran (40 ml), m-chlorobenzoic acid(834 ml) was added under ice cooling. The resulting solution was stirredat the same temperature for 1.5 hours. The reaction mixture wasdistilled off under reduced pressure. The residue thus obtained waspurified by column chromatography (SiO₂ 50 g, benzene:ethylacetate=6:1), whereby the title compound was obtained (yield: 1.44 g;38%).

NMR (CDCl₃, δ):

1.83-1.90(4H,m), 3.00-3.62(2H,ABq,J=18 Hz), 3.21-3.25(2H,m),3.35-3.39(2H,m), 4.41-4.43(1H,m), 4.72,5.32(2H,ABq,J=13 Hz),6.30(1H,dd,J=5 Hz,9 Hz), 6.42(1H,s), 6.93(1H,s), 7.35-7.40(40H,m)

PREPARATION EXAMPLE 40 Benzhydryl7-[(Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-pyrrolidinyl) carbonyloxymethyl-3-cephem-4-carboxylate##STR86##

To a solution of the compound (1.44 g), which had been obtained inPreparation Example 39, in N,N-dimethylformamide (15 ml), phosphorustrichloride (0.43 ml) was added at -30° C. The resulting solution wasstirred at the same temperature for 30 minutes.

The reaction mixture was poured into ethyl acetate, which had beencooled to -78° C. in advance, followed by the addition of water. Theethyl acetate layer was collected, washed with water and a saturatedaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. Then, the solvent was distilled off under reduced pressure. Theresidue thus obtained was dissolved in ethyl acetate and the resultingsolution was added to isopropyl ether. The resulting precipitate wascollected by filteration and washed with isopropyl ether, whereby thetitle compound was obtained (yield: 895 mg, 63%).

NMR (CDCl₃, δ):

1.84-1.87 (4H,m), 3.28-3.50(2H,ABq,J=18 Hz), 3.20-3.24(2H,m),3.35-3.38(2H,m), 4.82,5.10(2H,ABq, J=13 Hz), 5.05(1H,d,J=5 Hz),6.09(1H,dd,J=5 Hz,9 Hz), 6.42(1H,s), 6.94(1H,s), 7.35-7.40(40H,m)

EXAMPLE 1 Sodium7-[(Z)-2)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylate ##STR87##

To the liquid mixture of trifluoroacetic acid (3 ml) and anisole (2 ml),benzhydryl 2-[(Z)-2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(1.4 g; 1.3 mmol), which had been obtained in Preparation Example 4, wasadded. The resulting solution was stirred for one hour. The reactionmixture was added with isopropyl ether (100 ml) and the resultingprecipitate was collected by filtration. The filtrate was added toformic acid (10 ml), followed by the reaction at room temperature for 2hours. Formic acid was distilled off under reduced pressure, followed bythe addition of ethyl ether. The resulting precipitate was collected byfiltration. The filtrate was purified by reversed-phase columnchromatography, whereby the title compound was obtained (yield: 240 mg,39%).

NMR (D₂ O, δ):

2.7(6H,br.s), 3.42,3.69(2H,ABq,J=19 Hz), 4.67,4.91(2H,ABq,J=12.6 Hz),5.22(1H,d,J=4.8 Hz), 5.85(1H,d,J=4.8 Hz), 7.00(1H,s)

EXAMPLE 2 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR88##

The compound, which had been obtained in Preparation Example 8, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 15%).

NMR (D₂ O, δ):

1.05-1.15(27/10H,m), 1.25-1.35(3/10H,m), 2.72(3/10H,br.s),2.90(27/10H,br.s), 3.05-3.15(2/10 Hm),3.25-3.40(18/10H,m),3.4-3.5(1H,m), 3.7-3.78(1H,m), 4.70-4.78(1H,m),4.90-5.00 (1H,m), 5.24-5.27(1H,m), 5.85-5.90(1H,m), 7.02(1H,s)

EXAMPLE 3 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-1-morpholyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR89##

The compound, which had been obtained in Preparation Example 12, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 15%).

NMR D₂ O, δ):

3.42,3.72(2H,ABq,J=18 Hz), 3.45-3.60(4H,m), 3.70-3.80(4H,m),4.75,4.95(2H,ABq,J=13 Hz), 5.23(1H,d,J=4.5 Hz), 5.86 (1H,d,J=4.5 Hz),7.01 (1H,s)

EXAMPLE 4 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR90##

To a solution of benzhydryl 7-((Z)-2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (1.46 g), which had been obtained in PreparationExample 13, in anisole (10 ml), trifluoroacetic acid (20 ml) was addeddropwise under ice cooling. At the same temperature, the resultingsolution was stirred for two hours and twenty minutes. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in methanol. The resulting solution was added with diisopropylether to precipitate crystals. The crystals precipitated were collectedby filtration and dissolved in methanol, followed by dissolution ofsodium acetate (600 mg). The resulting solution was added further withdiisopropyl ether to precipitate crystals. The crystals thusprecipitated were collected by filtration, washed with diisopropyl etherand then air-dried. The crystals thus obtained were purified byreverse-phase column chromatography, whereby sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (71 mg, 8.5%)was obtained.

NMR (D₂ O, δ):

2.65-2.80(6H,m), 3.26,3.52(2H,ABq,J=18.1 Hz), 3.83(3H,s),4.52,4.75(2H,ABq,J=12.6 Hz), 5.05(1H,d,J=4.8 Hz), 5.66(1H,d,J=4.8 Hz),6.85(1H,s)

EXAMPLE 5 Sodium7-[(Z)-2-(5-amino-1,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR91##

The compound, which had been obtained in Preparation Example 14, wastreated in a similar manner to Example 4, whereby the title compound wasobtained (yield: 27%).

NMR (D₂ O, δ):

2.68(6H,s), 3.21,3.46(2H,ABq,J=18.0 Hz),3.89(3H,s),4.50,4.72(2H,ABq,J=12.3 Hz), 5.01(1H,d,J=4.7 Hz), 5.67 (1H,d,J=4.7 Hz)

EXAMPLE 6 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-monofluoromethoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR92##

The compound, which had been obtained in Preparation Example 15, wastreated in a similar manner to Example 4, whereby the title compound wasobtained (yield: 10%).

NMR (D₂ O, δ):

2.62-2.73 (6H,m), 3.22,3.48 (2H,ABq,J=18.0 Hz),4.49,4.72(2H,ABq,d,J=12.8 Hz,1.6 Hz), 5.02-5.04(1H,m), 5.63-5.66(1H,m),5.61(2H,d,J=55.2 Hz), 6.95 (1H, s)

EXAMPLE 7

Sodium7-[(Z)-2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-piperidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR93##

The compound, which had been obtained in Preparation Example 19, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 28%).

NMR (D₂ O, δ):

1.25-1.47(6H,m), 3.17-3.29(4H,m), 3.25,3.51(2H,ABq,J=17.9 Hz),4.55,4.78(2H,ABq, J=12.5 Hz), 5.07(1H,d,J=4.6 Hz), 5.70(1H,d,J=4.6 Hz),6.82 (1H, s)

EXAMPLE 8 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR94##

The compound, which had been obtained in Preparation Example 23, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 25%).

NMR (D₂ O, δ):

2.00-2.10(2H,m), 3.21,3.47 (2H,ABq,J=17.9 Hz), 3.75-3.87(4H,m),4.51,4.70(2H,ABq,J=17.6 Hz), 5.05(1H,d,J=4.8 Hz), 5.68(1H,d,J=4.8 Hz),6.78(1H,s)

EXAMPLE 9 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl]-3-cephem-4-carboxylate ##STR95##

The compound, which had been obtained in Preparation Example 26, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 8.8%).

NMR (D₂ O, δ):

2.79-2.82(3H,m), 3.28-3.30(3H,m), 3.56-3.58 (3H,m), 4.57,4.75(2H,m),5.09(1H,d,J=5 Hz), 5.73(1H,d,J=5 Hz), 6.84(1H,s)

EXAMPLE 10 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR96##

The compound, which had been obtained in Preparation Example 29, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 21%).

NMR (D₂ O, δ):

2.85(3H,br.s), 3.28,3.55(2H,ABq,J=18 Hz), 4.1-4.25(2H,m), 4.5-4.9(2H,m),5.06(1H, d,J=5 Hz), 5.70(1H,d,J=5 Hz), 6.77(1H,s)

EXAMPLE 11 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(3-hydroxy-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR97##

The compound, which had been obtained in Preparation Example 33, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (yield: 17%).

NMR (D₂ O, δ):

2.05(2H,m), 3.25-3.8(6H,m), 4.4-4.5(1H, m), 4.6-4.95(2H,m),5.20(1H,d,J=5 Hz), 5.83(1H,d,J=5 Hz), 6.96(1H,s)

EXAMPLE 12 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-((S)-(+)-2-hydroxymethyl-1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR98##

The compound, which had been obtained in Preparation Example 37, wastreated in a similar manner to Example 1, whereby the title compound wasobtained.

NMR (D₂ O, δ):

1.70-1.84(4H,m), 3.19-3.82 (7H,m), 4.67 (2H,ABq,J=13 Hz),5.08(1H,d,J=4.8 Hz), 5.70 (1H,d,J=4.8 Hz), 6.83 (1H, s)

EXAMPLE 13 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR99##

The compound, which had been obtained in Preparation Example 40, wastreated in a similar manner to Example 1, whereby the title compound wasobtained (17%).

NMR (D₂ O, δ):

1.68-1.73(4H,m), 3.15-3.23(4H,m), 3.25, 3.52 (2H,ABq,J=18 Hz),4.52,4.75(2H,ABq,J=12 Hz), 5.15(1H,d,J=4 Hz), 5.68(1H,d,J=4 Hz),6.81(1H,s)

EXAMPLE 14 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidol]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR100##

Iodomethyl pivalate (37 mg; 0.16 mmol) was added to a solution of sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(80 mg; 0,162 mmol), which had been obtained in Example 1, indimethylformamide (2 ml), followed by stirring for one hour. After thereaction mixture was added with ethyl acetate (100 ml), the resultingmixture was washed with water and then with a saturated aqueous sodiumchloride solution, followed by drying over anhydrous magnesium sulfateand then by concentration under reduced pressure. The residue was addedwith isopropyl ether and solidified, whereby the title compound wasobtained (21 mg; yield: 23%).

NMR (CDCl₃, δ):

1.24(9H,s), 2.92(6H,br,s), 3.50,3.61(2H, ABq, J=19 Hz),4.89,5.17(2H,ABq,J=13 Hz), 5.07(1H,d, J=5 Hz ), 5.85,5.97 (1H, ABq,J=5.5 Hz ), 5.93 (1H, dd, J=5 Hz,8 Hz), 7.08(1H,S), 7.26(2H,S)

EXAMPLE 15 2-Ethylbutanoyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate ##STR101##

The compound obtained in Example 1 and iodomethyl 2-ethylbutyrate werereacted, whereby the title compound was obtained (yield: 63%).

NMR (CDCl₃,δ):

0.9(6H,t,J=7.4 Hz), 1.5-1.7 (4H,m), 2.25-2.35(1H,m), 2.93(6H,br.s),3.49,3.60(2H,ABq,J=18 Hz), 4.91,5.15 (2H,ABq,J=14 Hz), 5.07 (1H,d,J=5.0Hz), 5.84-5.95 (3H,m), 7.07 (1H,s)

EXAMPLE 16 1-(Isobutyloyloxy)ethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR102##

The compound obtained in Example 1 and 1-iodoethyl isobutyrate werereacted, whereby the title compound was obtained (yield: 10%).

NMR (CDCl₃, δ):

1.18(6H,d,J=7 Hz), 1.56(3H,d,J=5.5 Hz), 2.55-2.65(1H,m), 2.92(6H,s),3.50,3.51(together, 1H,d,J=18 Hz), 3.61,3.62(together, 1H,d,J=18 Hz),4.90,4.95(together, 1H,d,J=14 Hz), 5.05,5.07 (together, 1H,d,J=5 Hz),5.12,5.18(together, 1H,d,J=14 Hz), 5.88-5.95(1H,m), 7.00,7.10(together,1H,q,J=5.5 Hz), 7.09(1H,s)

EXAMPLE 17 1-(2-Ethylbutanoyloxy)ethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR103##

The compound obtained in Example 1 and 1-iodoethyl 2-ethylbutyrate werereacted, whereby the title compound was obtained (yield: 15%).

NMR (CDCl₃, δ):

0.90(3H,t,J=7 Hz), 0.91(3H,t,J=7 Hz), 1.5-1.75 (7H,m), 2.2-2.3(1H,m),2.92(6H,s), 3.48,3.53 (1H,d,J=18 Hz), 3.60,3.61(1H,d,J=18 Hz), 4.90,4.97(1H,d,J=14 Hz), 5.07(d,J=5 Hz), 5.14,5.15 (1H,d,J=14 Hz),5.88-5.95(1H,m), 7.00-7.10(1H,m), 7.08(1H,s)

EXAMPLE 18 1-(tert-Butylacetoxy)ethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR104##

The compound obtained in Example 1 and 1-iodoethyl tert-butylacetatewere reacted, whereby the title compound was obtained (yield: 4.5%).

NMR (CDCl₃, δ):

1.04(9H,s), 1.56(3H,d,J=5.5 Hz), 2.2-2.3 (2H,m), 2.93(6H,s),3.48,3.50(together,1H,d, J=18 Hz), 3.60,3.61(together, 1H,d,J=18 Hz)4.91,4.98(together, 1H,d,J=12 Hz), 5.03-5.10 (1H,m), 5.12,5.17(together,1H,d,J=12 Hz), 5.86-5.93(1H,m), 6.97-7.12(1H,m), 7.12 (1H,s)

EXAMPLE 19 1-(Ethoxycarbonyloxy)ethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR105##

The compound obtained in Example 1 and 1-iodoethyl ethylcarbonate werereacted, whereby the title compound was obtained.

NMR (CDCl₃, δ):

1.33(3H,t,J=7 Hz), 1.58-1.63(3H,m), 2.93(3H,br.s), 3.51(1H,d,J=18 Hz),3.61,3.62(together, 1H,d, J=18 Hz), 4.2-4.32(2H,m),4.91,5.17(1H,ABq,J=14 Hz), 4.99,5.22(1H,ABq,J=14 Hz), 5.05(0.5H,d,J=4.5Hz), 5.10(0.5H,d,J=4.5 Hz), 5.9-5.98(1H,m), 6.92(0.5H,q, J=5.5 Hz),7.04(0.5H,q,J=5.5 Hz),7.08(1H,s)

EXAMPLE 20 1-(Isopropyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR106##

The compound obtained in Example 1 and 1-iodoethyl isopropylcarbonatewere reacted, whereby the title compound was obtained (yield: 30%).

NMR (CDCl₃, δ):

1.26-1.37(6H,m), 1.58-1.62(3H,m), 2.93(6H,s), 3.50(1H,d,J=19 Hz),3.60,3.61(together, 1H,d,J=19 Hz), 4.9-5.24 (3H,m), 5.04,5.07 (together,1H,d,J=5 Hz), 5.93 (1H,dd,J=5 Hz,8 Hz), 6.92,7.02 (together, 1H,q, J=5.5Hz ), 7.08 (1H,s)

EXAMPLE 2 1-(Cyclohexylcarbonyloxy)ethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR107##

The compound obtained in Example 1 and 1-iodoethyl cyclohexylcarbonatewere reacted, whereby the title compound was obtained (yield: 19%).

NMR (CDCl₃, δ):

1.1-1.6(6H,m), 1.58-1.63(3H,m), 1.66-2.00(4H,m), 2.93(6H,s),3.52,3.40(2H,ABq,J=18 Hz), 4.6-4.7 (1H,m), 4.89,4.97(together, 1H,d,J=12Hz), 5.05-5.10(1H,m), 5.12, 5.17(together, 1H,d,J=12 Hz),6.83-6.94(1H,m), 6.89,6.98(together, 1H,q,J=5.5 Hz), 7.15 (1H, s)

EXAMPLE 22 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-ethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR108##

The compound obtained in Example 2 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 34%).

NMR (CDCl₃, δ):

1.12(3H,t,J=7 Hz), 1.24(9H,s), 2.89(#6/3H,s),2.90 (3/3H,s),3.25-3.35(2H,m), 3.47,3.48(together, 1H,d,J=18 Hz), 3.61(1H,d,J=18Hz),4.89(1H,d,J=13 Hz), 5.06(1H,d,J=5 Hz), 5.1-5.2(1H,m), 5.82,5.97(1H,ABq,J=5 Hz), 5.92(1H,dd,J=5 Hz,8 Hz), 7.07(1H,s)

EXAMPLE 23 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-morpholinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR109##

The compound obtained in Example 3 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 24%).

NMR (CDCl₃, δ):

3.45-3.50 (5H,m), 3.58-3.70(5H,m),4.89,5.18 (2H,ABq,J=12 Hz),5.07(1H,d,J=5 Hz), 5.84,5.97 (2H,ABq,J=5 Hz), 5.93(1H,dd,J=5 Hz,8 Hz),7.08(1H,s)

EXAMPLE 24 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR110##

The compound obtained in Example 4 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 65%).

NMR (CDCl₃, δ):

1.23(9H,S), 2.92(6H,S), 3.50,3.60(2H,ABq,J=18.7 Hz), 4.09(3H,S),4.84,5.16(2H,ABq,J=14 Hz), 5.09(1H,d, J=4.8 Hz), 5.85-5.95(2H,m),5.99-6.03(1H,m), 6.92(1H,s), 7.49(1H,d,J=7.5 Hz)

EXAMPLE 25 Pivaloyloxymethyl7-[(Z)-2-(5-amino-1,2,4-thiazol-3-yl)-2-methoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR111##

The compound obtained in Example 5 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 70%).

NMR (CDCl₃, δ):

1.13 (9H, s), 2.92(6H,s), 3.50,3.59(2H,ABq,J=18.6 Hz), 4.12 (3H, s),4.84,5.19(2H,ABq,J=13.7 Hz), 5.10(1H,d, J=4.8 Hz ), 5.85-5.94(2H,m),6.12-6.16(1H,m), 6.42(1H, s)

EXAMPLE 26 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-monofluoromethoxyaminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR112##

The compound obtained in Example 6 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 70%).

NMR (CDCl₃, δ):

1.14(9H,s), 2.91(6H,s), 3.50,3.60(2H,ABq,J=18.4 Hz),4.85,5.16(2H,ABq,J=14.2 Hz), 5.10(1H,d,J=4.8 Hz),5.65-6.00(3H,m),5.86,5.93(2H,ABq,J=5.5 Hz), 6.98(1H,s)

EXAMPLE 27 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-piperidinylcarbonyloxymethyl-3-cephem-4-carboxylate##STR113##

The compound obtained in Example 7 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 59%).

NMR (CD₃ OD, δ):

1.13(9H,s), 1.48-1.66(6H,m), 3.37-3.46(4H,m), 3.54,3.69(2H,ABq,J=18.4Hz), 4.77,5.13(2H,ABq, J=13.4 Hz), 5.20(1H,d,J=4.9 Hz),5.84,5.93(2H,ABq, J=6 Hz), 5.92(1H,d,J=4.9 Hz), 6.76(1H,s)

EXAMPLE 28 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR114##

The compound obtained in Example 8 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 54%).

NMR (CDCl₃, δ):

2.24-2.30(2H,m), 3.47,3.60(2H,ABq,J=18.4 Hz), 3.95-4.10(4H,m),4.87,5.12(2H,ABq,J=14.1 Hz), 5.06(1H, d,J=5.1 Hz), 5.91(2H,ABq,J=5.6Hz), 5.90-5.93(1H,m), 7.07(1H,S)

EXAMPLE 29 1-(Isopropyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR115##

The compound obtained in Example 8 and iodoethyl isopropylcarbonate werereacted, whereby the title compound was obtained (yield: 27%).

NMR (CDCl₃, δ):

1.30-1.35(6H,m), 2.22-2.31(2H,m), 3.45-3.65(2H,m), 4.00-4.06(4H,m),4.89-5.20(4H,m), 5.90-5.93(1H,m), 6.92(1/2H,q,J=5.5 Hz),7.03(1/2H,q,J=5.5 Hz), 7.08 (1H,s)

EXAMPLE 30 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR116##

The compound obtained in Example 9 and iodomethyl pivalate were reacted,whereby the title compound was obtained (yield: 57%).

NMR (CDCl₃, δ):

1.21-1.25(9H,m), 2.97 (3H,s), 3.41-3.45 (2H,m), 3.46-3.60(2H,m),3.71-3.77(2H,m), 4.82-4.95(2H,m), 5.05-5.08(1H,m),5.86,5.95(2H,ABq,J=6Hz), 5.88-5.91 (1H, m), 7.00(1H,s)

EXAMPLE 31 1-Cyclohexyloxycarbonyloxyethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2-hydroxyethyl)-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR117##

The compound obtained in Example 9 and 1-iodoethyl cyclohexylcarbonatewere reacted, whereby the title compound was obtained (yield: 28%).

NMR (CDCl₃, δ):

1.4-1.6(6H,m),1.62-1.72(3H,m), 1.83-1.92(4H,m), 2.93(3H,s),3.38-3.41(2H,m),3.42-3-50(2H,m), 3.70-3.75(2H,m), 4.57-4.61(1H,m),4.99(1H,q,J=5 Hz), 5.05-5.14(2H,m), 5.82-5.86(1H,m), 6.85,6.96(1H,ABq,J:5 Hz), 6.99(1H,s)

EXAMPLE 32 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-cyanomethyl-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR118##

The compound obtained in Example 10 and iodomethyl pivalate werereacted, whereby the title compound was obtained (yield: 70%).

NMR (CDCl₃, δ):

1.1-1.25(9H,m),3.01(3H,s), 3.4-3.65(2H,m), 4.2-4.3(2H,m),4.8-5.25(3H,m),5.8-6.0(3H,m), 6.90(1H, br.s), 7.30(2H,s)

EXAMPLE 33 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(S)-(+)-2-hydroxymethyl-1-pyrrolidinyl]carbonyloxymethyl-3-cephem-4-carboxylate##STR119##

The compound obtained in Example 12 and iodomethyl pivalate werereacted, whereby the title compound was obtained.

NMR (CD₃ OD, δ):

1.83-2.00(4H,m), 3.30-3.87(7H,m), 5.01(2H,ABq, J=14 Hz), 5.20(1H,d,J=4.8Hz), 5.84 (1H,d,J=4.8 Hz), 5.91-5.94(2H,m), 6.76(1H,s)

EXAMPLE 34 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-pyrrolidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR120##

The compound obtained in Example 13 and iodomethyl pivalate werereacted, whereby the title compound was obtained (yield: 28%).

NMR (CDCl₃, δ):

1.16-1.21(9H,m), 1.80-1.85(4H,m), 3.30-3.39(4H,m), 3.50-3.60(2H,m),4.80-4.90,5.05,5.13(2H,m), 5.02-5.04(1H,m),5.75-5.80(2H,m),5.85-5.91(1H,m), 6.98 (1H,s)

EXAMPLE 35 1-Acetoxyethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N,N-dimethylaminocarbonyloxymethyl-3-cephem-44-carboxylate##STR121##

The compound obtained in Example 1 and 1-bromoethyl acetate werereacted, whereby the title compound was obtained (yield: 14%).

NMR (CDCl₃, δ):

1.55-1.58(3H,m), 2.11(3H,d,J=4.6 Hz), 2.92-2.95 (3H,s), 3.47-3.65(2H,m),4.83-5.24(3H,m), 5.83-5.94(1H,m), 6.98-7.15(2H,m)

EXAMPLE 36 1-(Cyclohexyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate ##STR122##

The compound obtained in Example 8 and 1-iodoethyl cyclohexylcarbonatewere reacted, whereby the title compound was obtained (yield: 27%).

NMR (CDCl₃, δ):

1.24(3H,d,J=7.2 Hz), 1.75-1.80(10H,m),2.25-2.32(2H,m), 3.45-3.65(2H,m),4.00-4.06(4H,m), 4.91,4.98(1H,ABq,J=13.8 Hz), 5.03-5.07(1H,m),5.10-5.13(1H,m), 5.09,5.18(1H,ABq,J=13.8 Hz), 5.90-5.93(1H,m),6.93(1/2H,q,J=5.5 Hz), 7.03(1/2H,q,J=5.5 Hz), 7.08(1H,s)

EXAMPLE 37 1-Acetoxyethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-azetidinyl)carbonyloxymethyl-3-cephem-4-carboxylate##STR123##

The compound obtained in Example 8 and 1-bromoethyl acetate werereacted, whereby the title compound was obtained.

NMR (CDCl₃, δ):

1.54-1.56 (3H,m), 2.10-2.21 (3H,m), 2.20-2.35 (2H,m), 3.45-3.65(2H,m),3.95-4.08 (4H,m), 4.85-4.95(1H,m), 5.05-5.1 (2H, m), 5.87-5.95(1H,m),6.97-7.17 (2H,m)

PREPARATION EXAMPLE 41 Benzhydryl7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate##STR124##

To a suspension of benzhydryl7-phenylacetamide-3-hydroxymethyl-3-cephem-4-carboxylate (15.8 g; 0.031mol) and p-nitrophenylchloroformate (6.19 g; 0.031 mol) intetrahydrofuran (160 ml), pyridine (2.43 g; 0.031 mol) was addeddropwise under ice cooling, followed by stirring at the same temperaturefor 25 minutes.

The reaction mixture was poured into a mixed solvent of ethyl acetateand water and the ethyl acetate layer was collected. The resulting ethylacetate layer was washed with a saturated aqueous sodium chloridesolution and dried over magnesium sulfate. Then, the solvent wasdistilled off under reduced pressure. The residue was added withdiisopropyl ether and triturated. The resulting mixture was filtered sothat the solid was collected. The solid was dried in air, wherebybenzhydryl7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylatewas obtained (yield: 18.8 g; 90.2%).

NMR (CDCl₃, δ):

3.40,3.60(2H,ABq,J=18.5 Hz), 3.61,3.66(2H,ABq, =13.6 Hz),4.97(1H,d,J=8.8 Hz), 4.97,5.24 (2H,ABq,J=13.2 Hz), 5.88(1H,dd,J=4.9Hz,8.8 Hz), 6.30(1H,d,J=8.8 Hz), 6.92(1H,s), 7.24-7.42(17H,m),8.23-8.28(2H,m)

PREPARATION EXAMPLE 427-Phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylicacid ##STR125##

To a solution of benzhydryl7-phenylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate(6.79 g, 0.01 mol) in dichloromethane (14 ml), trifluoroacetic acid (17ml) was added dropwise under ice cooling, followed by stirring for 50minutes. The reaction mixture was poured into diisopropyl ether. Theprecipitate thus obtained was collected by filtration, washed withdiisopropyl ether and dried in air, whereby7-phenylacetamido-3-p-nitrophenoxy-carbonyloxymethyl-3-cephem-4-carboxylic acid was obtained (yield: 4.50g; 87.7%). NMR (DMSO, δ): 3.49,3.57(2 H,ABq,J=14.0 Hz), 3.60,3.71(2H,ABq, =18.1 Hz), 4.95,5.24 (2 H,ABq,J=12.5 Hz), 5.12(1 H,d, J=4.9 Hz),5.72(1 H,dd,J=4.9,8.6 Hz), 7.19-7.28(5 H,m), 7.53-7.58(2 H,m),8.28-8.35(2 H,m), 9.12 (1 H,d,J=8.6 Hz)

PREPARATION EXAMPLE 43

Sodium7-phenylacetamido-3-N,N-dimethylcarbamoyl-oxymethyl-3-cephem-4-carboxylate##STR126##

To a solution of benzhydryl7-phenylacetamide-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylate(5.13 g, 0.01 mol) in tetrahydrofuran (36 ml) and water (4 ml), a 50%aqueous solution of dimethylamine (1.8 g; 0.02 mol) was added dropwiseunder ice cooling. At the same temperature, the resulting solution wasstirred for 10 minutes. The reaction mixture was poured into a mixtureof ethyl acetate and 1N hydrochloric acid and an organic layer wascollected. The organic layer was washed successively with water and asaturated aqueous sodium chloride solution, followed by drying overmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was suspended in methanol and the resulting suspension wasadded with a solution of sodium acetate (984 mg; 0.012 mol) in methanol.The vlrst solution thus obtained was concentrated under reducedpressure. The concentration was stopped when a precipitate had appeared.After the addition of 2-propanol, the precipitate was collected byfiltration and dried in air, whereby sodium7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (yield: 2.25 g; 51.0%). NMR (D₂ O, δ): 2.74(6 H,s),3.21,3.47(2 H,ABq,J=17.9 Hz), 3.51,3.57 (2 H,ABq,J=14.8 Hz), 4.51,4.74(2 H,ABq,J=12.6 Hz), 4.92(1 H,d,J=4.6 Hz), 5.48(1 H,d,J=4.6 Hz),7.18-7.28(5 H,m)

PREPARATION EXAMPLE 44

1-(Isopropoxycarbonyloxy)ethyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR127##

To a solution of sodium7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(2.2 g; 5 mmol) in N,N-dimethylformamide (20 ml),isopropyl-1-iodoethylcarbonate (1.29 g; 5 mmol) was added under icecooling, followed by stirring at the same temperature for 30 minutes.The reaction mixture was poured into a mixture of ethyl acetate andwater and the ethyl acetate layer was collected. The ethyl acetate layerwas successively washed with water and a saturated aqueous sodiumchloride solution, followed by drying over magnesium sulfate. Then, thesolvent was distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column, whereby1-(isopropoxycarbonyloxy)ethyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (yield: 1.43 g; 52.1%). NMR (CDCl₃, δ) 1.22-1 29(6 H,m) ,1.26(3 H,d,J=5.5 Hz), 2.85(6 H,s), 3.35,3.48(1 H,ABq,J=18.4 Hz),3.36,3.49(1 H,ABq, J=18.4 Hz), 3.55(2 H,s), 4.75-4.88(3 H,m), 5.04,5.10(2 H,ABq,J=13.9 Hz), 5.71-5.76(1 H,m), 6.77-6.82 (1 H,m) , 6.91(0.5H,q,J=5.5 Hz), 6.94(0.5 H,d,J=8.9 Hz), 7.19-7.29 (5 H,m)

EXAMPLE 38 Benzhydryl7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR128##

To a solution of trichloromethylchloroformate (0.3 ml; 2.5 mmol) intetrahydrofuran (10 ml), a solution of benzhydryl7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate (2.12 g; 5 mmol) andpyridine (0.395 g; 5 mmol) in tetrahydrofuran (15 ml) was added underice cooling. After 70 minutes, the resulting solution was added dropwisewith a tetrahydrofuran solution (1 ml) containing dimethylamine (0.45 g;5 mmol) dissolved therein, followed by stirring for 25 minutes. Thereaction mixture was added with ethyl acetate (50 ml). The organic layerwas washed with water, dried over magnesium sulfate and concentratedunder reduced pressure. The residue thus obtained was purified bychromatography on a silica gel column, whereby the target compound wasobtained (yield: 1.1 g; 44%). NMR (CDCl3, δ): 2.82(3 H,s), 2.88(3 H,s),3.42,3.57(2 H,ABq,J=18.4 Hz), 4.82,5.09(2 H,ABq,J=13.9 Hz), 4.97(1H,d,J=4.8 Hz), 5.91(1 H,dd,J=4.8 Hz,9.3 Hz), 6.66(1 H,d,J=9.3 Hz),6.94(1 H,s), 7.25,7.45(10 H,m), 8.20(1 H,s)

EXAMPLE 397-Amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid##STR129##

Sodium7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (5.0g; 14.25 mmol) was dissolved in methanol (45 ml). To the resultingsolution, a methanol solution (30 ml) containing concentratedhydrochloric acid (10 ml) dissolved therein was added at roomtemperature. After stirring for three hours, the reaction mixture wasconcentrated under reduced pressure. The concentrate was added withwater (50 ml). Under ice cooling, the resulting solution was controlledto pH 2.8 with a 1N caustic soda solution. A precipitate thus formed wascollected by filtration, whereby the title compound was obtained (yield:1.82 g; 42%). NMR (DMSO-d6, δ): 2.81(3 H,s), 2.82(3 H,s), 3.45,3.58(2H,ABq,J=18.1 Hz), 4.60,4.98(2 H,ABq,J=13.0 Hz), 4.77-4.80(1 H,m) ,4.97-5.00(1 H,m)

EXAMPLE 40 1-(Isopropoxycarbonyloxy)ethyl7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylatehydrochloride ##STR130##

In tetrahydrofuran (440 ml), 1-(isopropoxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylatehydrochloride (22 g; 47 mmol) was dissolved, to whichN,O-bistrimethylsilylacetamide (35 ml) was added.

To the resulting solution,2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetic chloride hydrochloride(15.8 g) was gradually added under ice cooling.

The reaction mixture was heated tack to room temperature, at which itwas stirred for 30 minutes. The reaction mixture was added with ethylacetate (600 ml), water (40 ml) and saturated aqueous sodium chloridesolution (25 ml) and the organic layer was collected. The organic layerwas then washed with saturated aqueous sodium chloride solutions anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, whereby the title compound was obtained (yield:31.5 g; 99%). NMR (CD₃ OD, δ): 1.27-1.29(6 H,m), 1.54(3 H,d,J=5.5 Hz),2.23(3 H,s) , 2.92(6 H,d,J=8.4 Hz), 3.60(1 H,d,J=18 Hz), 3.74(1 H,dd,J=9 Hz,18 Hz), 4.81-5.16(3 H,m), 5.22(1 H,dd, J=5 Hz,12 Hz), 5.97(1H,dd,5 Hz,15 Hz), 6.85(0.5 H,dd, J=5 Hz,10 Hz) , 6.94(0.5 Hz,dd,J=5Hz,10 Hz) , 7.19(1 H,s)

EXAMPLE 41 1-(Isopropoxycarbonyloxy)ethyl7β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylatehydrochloride ##STR131##

In methanol (108 l), 1-(isopropoxycarbonyloxy)ethyl7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylate(10.8 g; 15.9 mmol), which had been obtained in Example 40, wasdissolved, to which concentrated hydrochloric acid (8.6 ml) was addeddropwise under ice cooling. After the dropwise addition was completed,the resulting solution was stirred at room temperature for 3 hours. Thereaction mixture was added with ethyl acetate (540 ml). The organiclayer was washed with water, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residue was added withisopropyl ether and the resulting solid was collected by filtration,whereby the title compound was obtained (yield: 8 g; 80%).

The compound obtained in this Example conformed in HPLC and TLC datawith the compound obtained in Example 20. NMR (CD₃ OD, δ): 1.27 1.29(6H,m), 1.54(3 H,d,J=5.5 Hz), 2.91(3 H,s), 2.93(3 H,s), 3.57,3.67(1H,ABq,J=14.7 Hz), 3.57,3.69 (1 H,ABq,J=14.7 Hz), 4.78 4.9(2 H,m),5.06(0.5 H,d, J=13.6 Hz), 5.17(0.5 Hz,d,J=13.4 Hz), 5.19(0.5 H,d, J=5Hz), 5.22(0.5 H,d,J=5 Hz), 5.91(0.5 H,d,J=5 Hz), 5.95(0.5 H,d,J=5 Hz),6.85(0.5 H,q,J=5.5 Hz), 6.94(0.5 H,q,J=5.5 Hz), 6.97 (1 H,s)

EXAMPLE 427β-[2-(2-Aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylicacid ##STR132##

In ethyl acetate (4 ml),7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (0.2g; 0.66 mmol) was suspended. To the suspension,N,O-bistrimethylsilylacetamide (0.49 ml) was added and dissolved.

To the resulting solution,2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetic acid chloridehydrochloride (0.189 g; 0.664 mmol) was added gradually under icecooling.

The reaction mixture was heated back to room temperature, at which itwas stirred for 30 minutes. Methanol (0.2 ml) was added to the resultingsolution, followed by concentration under reduced pressure. The residuethus obtained was purified by reversed phase column chromatography,whereby the title compound was obtained (yield: 138 mg; 41%).

EXAMPLE 43 1-(Isopropoxycarbonyloxy)ethyl7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylate##STR133##

In ethyl acetate (30 ml),7β-[2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylicacid (2.17 g; 4.24 mmol), which had been obtained above, was dissolved.To the resulting solution, dicyclohexylamine (1.35 ml) was added and theresulting precipitate was collected by filtration. Dicyclohexylaminesalt thus obtained (1.7 g; 2.45 mmol) was dissolved inN,N-dimethylacetamide (10 ml). To the resulting solution,1-iodoethylisopropyl carbonate (758 mg; 2.94 mmol) was added under icecooling, followed by stirring for one hour. The reaction mixture wasadded with ethyl acetate, washed with water and then dried overmagnesium sulfate. After concentration under reduced pressure, theconcentrate was added with isopropyl ether and the resulting solid wascollected by filtration, whereby the title compound was obtained. Thecompound obtained in this Example conformed in HPLC and TLC data withthe compound obtained in Example 40.

EXAMPLE 44 Sodium7β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylate##STR134##

In ethyl acetate (10 ml),7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (0.5g; 1.66 mmol) was suspended. To the suspension,N,O-bistrimethylsilylacetamide (1.23 ml) was added and dissolved.

To the resulting solution,2-(2-aminothiazol-4-yl)-2-(Z)-acetoxyiminoacetic acid chloridehydrochloride (0.52 g; 1.83 mmol) was gradually added under ice cooling.

The reaction mixture was heated back to room temperature, at which itwas stirred for 30 minutes. Then, methanol (0.5 ml) and ethyl acetate(10 ml) were added to the reaction mixture and the precipitate thusobtained was collected by filtration. The resulting precipitate wasdissolved in methanol (5 ml), followed by the addition of concentratedhydrochloric acid (0.5 ml) and then by stirring for 30 minutes. Afterconcentration, the reaction mixture was controlled to pH 7 with anaqueous sodium hydrogencarbonate solution and then purified by reversedphase column chromatography, whereby the title compound was obtained(yield: 349 mg; 50%).

The compound in this example conformed with the compound obtained inExample 1 in physicochemical properties such as N.M.R. spectrum, HPLCand TLC.

PREPARATION EXAMPLE 45 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR135##

Added to benzhydryl were7-formamido-3-monomethylcarbamoyloxymethyl-3-cephem-4-carboxylate (3.54g), tetrahydrofuran (40 ml) and methanol (40 ml). Then, the resultingsolution was added with concentrated hydrochloric acid (3.6 ml) at roomtemperature, followed by stirring at the same temperature for 3 hours.The reaction mixture was concentrated under reduced pressure. Theresidue obtained was diluted with ethyl acetate, followed by washingwith a saturated aqueous solution of sodium bicarbonate and a saturatedaqueous sodium chloride solution and then by drying over anhydrousmagnesium sulfate. The solvent was then distilled off.

At room temperature, the residue thus obtained was added with a solutionwhich had separately been obtained by adding2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (4.9 g),dicyclohexylcarbodiimide (1.52 g) and 1-hydroxy-1H-benztriazole (1.0 g)to tetrahydrofuran (30 ml) and stirring them for 30 minutes. After theresulting solution was stirred overnight at room temperature, thereaction mixture was filtered. The filtrate was diluted with an aqueoussolution of ethyl acetate. The diluted filtrate was washed further with1N hydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution, followed by drying overanhydrous magnesium sulfate. The solvent was then distilled off. Theresidue thus obtained was purified by column chromatography (SiO₂ ;benzene:ethyl acetate=6:1), whereby the title compound was obtained(yield: 5.39 g; 66%). NMR (CDCl₃, δ): 2.75(3 H,d,J=5 Hz), 3.25,3.52 (2H,ABq,J=18 Hz), 4.40(1 H,d,J=5 Hz), 4.77,5.07 (2 H,ABq,J=14 Hz), 5.05(1H,d,J=5 Hz), 6.10 (1 H,dd,J=5 Hz,9 Hz), 6.43(1 H,s), 6.97(1 H,s),7.21-7.39(40 H,m)

PREPARATION EXAMPLE 46 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-N-(2-methoxyethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR136##

In a similar manner to Preparation Example 45, the title compound wasobtained (yield: 53%). NMR (CDCl₃, δ): 3.32-3.38(5 H,m), 3.42(2 H,t,J=5Hz), 3.25,3.49 (2 H,ABq,J=18 Hz), 4.78,5.05(2 H,ABq,J=12 Hz), 5.08(1H,d,J=5 Hz), 6.1(1 H,dd,J=5 Hz,9 Hz), 6.42(1 H,s), 6.94(1 H,s),7.3-7.4(40 H,m)

PREPARATION EXAMPLE 47 Benzhydryl7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyacetamido]-3-N-(2-monofluoroethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR137##

In a similar manner to Preparation Example 45, the title compound wasobtained. NMR (CDC₃, δ): 3.1-3.4(4 H,m), 4.2-4.4(2 H,m), 4.85(2H,ABq,J=14 Hz), 4.92(1 H,d,J=4.9 Hz), 6.04(1 H,dd,J=4.9 Hz,8.9 Hz),6.44(1 H,s), 6.95(1 H,s), 7.1-7.5(40 H,m)

PREPARATION EXAMPLE 48 Benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyacetamido]-3-N-(2,2,2-trifluoroethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR138##

In a similar manner to Preparation Example 45, the title compound wasobtained. NMR (CDCl₃): 3.21(2 H,ABq,J=19 Hz), 3.52-3.58(2 H,m), 4.88(2H,ABq, J=14 Hz) , 4.91(1 H,d,J=4.9 Hz), 6.03(1 H,dd,J=4.9 Hz, 8.8 Hz),6.45(1 H,s), 6.95(1 H,s), 7.13-7.47(40 H,m)

EXAMPLE 45 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-methylcarbamoyloxymethyl-3-cephem-carboxylate##STR139##

To a solution of the compound (5.35 g), which had been obtained inPreparation Example 45, in anisole (25 ml), trifluoroacetic acid (20 ml)was added under ice cooling, followed by stirring at the sametemperature for one hour. The reaction mixture was added with isopropylether and the precipitate was collected by filtration. The powdery solidthus obtained was added with formic acid (35 ml), followed by stirringat room temperature for one hour. The solvent was distilled off underreduced pressure and the residue was diluted with methanol. Theresulting solution was added with sodium acetate (1.0 g), and methanolwas distilled off. The residue thus obtained was diluted with ethylacetate and then, formed into powder in isopropyl ether. The powder thusobtained was purified by liquid chromatography, whereby the titlecompound was obtained (yield: 326 mg; 14%). NMR (D₂ O,δ): 2.54(3 H,s),3.21,3.51(2 H,ABq,J=18 Hz), 4.60,4.70 (2 H,ABq,J=18 Hz), 5.06(1H,d,J=4.8 Hz), 5.69(1 H,d, J=4.8 Hz), 6.83(1 H,s)

EXAMPLE 46 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-N-(2-methoxyethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR140##

The compound, which had been obtained in Preparation Example 46, wastreated in a similar manner to Example 45, whereby the title compoundwas obtained (yield: 46%). NMR (D₂ O,δ): 3.17(2 H,t,J=5 Hz), 3.20(3H,s), 3.26,3.53(2 H, ABq,J=18 Hz), 3.40(2 H,t,J=5 Hz), 4.55,4.76(2 H,ABq,J=12 Hz) , 5.09(1 H,d,J=5 Hz), 5.71(1 H,d,J=5 Hz),

EXAMPLE 47 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2-monofluoroethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR141##

The compound, which had been obtained in Preparation Example 47, wastreated in a similar manner to Example 45, whereby the title compoundwas obtained. NMR (D₂ O,δ): 3.2-3.5(4 H,m), 4.2-4.4(2 H,m), 4.65(2H,ABq,J=12 Hz), 5.05(1 H,d,J=4.8 Hz), 5.68(1 H,d,J=4.8 Hz), 6.80(1 H,s)

EXAMPLE 48 Sodium7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2,2,2-trifluoroethyl)carbamoyloxymethyl-3-cephem-4-carboxylate##STR142##

The compound, which had been obtained in Preparation Example 48, wastreated in a similar manner to Example 45, whereby the title compoundwas obtained. NMR (D₂ O,δ): 3.39(2 H,ABq,J=18 Hz), 3.66-3.73(2 H,m),4.71(2 H, ABq,J=13 Hz), 5.08(1 H,d,J=4.8 Hz), 5.70(1 H,d, J=4.8 Hz),6.81(1 H,s)

EXAMPLE 49 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR143##

To a solution of the compound (106 mg), which had been obtained inExample 45, in N,N-dimethylacetamide (2 ml), iodomethyl pivalate (51 mg)was added, followed by stirring at the same temperature for one hour.The reaction mixture was added with ethyl acetate and water. Then, theethyl acetate layer was collected and washed with saturated aqueoussodium chloride solution, followed by drying over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue thus obtained was dissolved in ethyl acetate and the resultingsolution was added with isopropyl ether. A precipitate so formed wascollected by filtration and washed with isopropyl ether, whereby thetitle compound was obtained (yield: 44 mg; 35%). NMR (CDCl₃,δ):1.13-1.15(9 H,m), 2.70(3 H,s), 3.42-3.59(2 H,m), 4.72-4.76(1 H,m),4.95-5.05(2 H,m), 5.78-5.81(1 H,m), 5.81-5.89(2 H,m), 6.93(1 H,s)

EXAMPLE 50 1-(Isopropoxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-methylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR144##

In a similar manner to Example 49, the title compound was obtained(yield: 55%). NMR (CD₃ OD,δ): 1.25-1.35(9 H,m), 1.51-1.57 (3 H,m),2.70(3 H,s), 3.48-3.70(2 H,m), 4.75-4.90(1 H,m), 5.02-5.09(1 H,ABq, J=14Hz), 5.16-5.21(1 H,m), 5.90-5.95(1 H,m), 6.75(1 H,s), 6.84-6.95(1 H,m)

EXAMPLE 51 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2-methoxyethyl)carbamoyloxymethyl-3-cephem-4-carboxylate##STR145##

The compound, which had been obtained in Preparation Example 46, wastreated in a similar manner to Example 49, whereby the title compoundwas obtained. NMR (CDCl₃,δ): 1.26-1.28(9 H,m), 3.36-3.40(5 H,m),3.47-3.50(3 H,m), 3.62(1 H,d,J=18 Hz), 4.84,5.10(2 H,ABq,J=13 Hz),5.04(1 H,d,J=3.5 Hz), 5.86,5.96(2 H,ABq,J=5 Hz), 5.91-5.94(1 H,m),7.05(1 H,s)

EXAMPLE 52 Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2-monofluoroethyl)-carbamoyloxymethyl-3-cephem-4-carboxylate##STR146##

The compound, which had been obtained in Preparation Example 47, wastreated in a similar manner to Example 49, whereby the title compoundwas obtained. NMR (CD₃ OD,δ): 1.22(9 H,s), 3.3-3.4(2 H,m), 3.63(2H,ABq,J=18 Hz), 4.35-4.50(2 H,m), 4.96(2 H,ABq,J=13 Hz), 5.20(1H,d,J=4.8 Hz), 5.83-5.94(3 H,m), 6.76(1 H,s)

EXAMPLE 53

Pivaloyloxymethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-N-(2,2,2-trifluoroethyl)ethyl)carbamoyloxymethyl-3-cephem-4-carboxylate##STR147##

The compound, which had been obtained in Preparation Example 48, wastreated in a similar manner to Example 49, whereby the title compoundwas obtained. NMR (CD₃ OD,δ): 1.21(9 H,s), 3.61(2 H,ABq,J=18 Hz),3.74-3.81(2 H,m), 5.00(2 H,ABq,J=14 Hz), 5.19(1 H,d,J=4.9 Hz),5.83-5.94(3 H,m), 6.76(1 H,s).

EXAMPLE 54 Sodium 7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate ##STR148##

Benzhydryl7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (139g) was dissolved in methylene chloride (1.4 l). The resulting solutionwas added with anisole (69.5 ml) and trifluoroacetic acid (348 m l),followed by stirring for 30 minutes. After the reaction, the solvent wasdistilled off under reduced pressure. After the residue thus obtainedwas dissolved in a small amount of ethyl acetate, trituration wasapplied in a mixed solvent of diisopropyl ether and diethyl ether.Crystals precipitated were collected by filtration. Then, the crystalswere dissolved in methanol (500 ml), followed by the addition of sodiumacetate (34.5 g) and isopropyl alcohol (500 ml). The resulting crystalswere collected by filtration. After the crystals were washed withdiisopropyl ether, they were air-dried, whereby the title compound wasobtained (yield: 80.2 g; 82%). NMR (D₂ O,δ):

2.75(6 H,s), 3.30,3.53(2 H,ABq,J=18.1 Hz), 4.53,4.81(2 H,ABq,J=12.8 Hz),5.00(1 H,d,J=4.8 Hz), 5.61 (1 H,d,J=4.8 Hz), 8.08(1 H,s)

EXAMPLE 55 1- (Isopropoxycarbonyloxy)ethyl7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR149##

After the compound (84 g), which had been obtained in Example 54, wasdissolved in dimethyl formamide (420 ml), the resulting solution wasadded with iodo-1-isopropoxycarbonyloxyethane (61.7 g) under icecooling, followed by stirring for 2 hours. After the reaction, thereaction mixture was poured into a mixed solvent of water and ethylacetate. The resulting mixture was allowed to stand and the organiclayer was collected. The resulting organic layer was washed with water,a 10% aqueous solution of sodium thiosulfate and saturated aqueoussodium chloride solution, followed by drying over magnesium sulfate. Thesolvent was distilled off under reduced pressure. Then, the residue wassubjected to column chromatography, whereby the title compound wasobtained (yield: 44.7 g; 40%). NMR (CDCl₃, δ): 1.29-1.34(6 H,m),1.57-1.59(3 H,m), 2.91(6 H,s), 3.46-3.62(2 H,m), 4.86-5.22(4 H,m),5.88-5.95(1 H,m), 6.39(0.5 H,d,J=9.3 Hz), 6.47(0.5 H,d,J=9.2 Hz),6.88-6.92(0.5 H,m), 6.98-7.02(0.5 H,m), 8.27(0.5 H,s), 8.28(0.5 H,s)

EXAMPLE 56 1-(Isopropoxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatehydrochloride ##STR150##

After the compound (44.2 g), which had been obtained in Example 55, wasdissolved in a mixed solvent of methanol (440 ml) and tetrahydrofuran(220 ml), the resulting solution was added with concentratedhydrochloric acid (45 ml), followed by stirring at room temperature for5 hours. After the reaction, the solvent was distilled off under reducedpressure. The residue was poured into a mixed solvent of water and ethylacetate and the resulting solution was adjusted to pH 6.5 with aqueoussodium bicarbonate solution. The organic layer was collected and thenwashed with saturated sodium chloride solution. After the organic layerwas dried over sodium sulfate, a solution of hydrochloric acid in ethylacetate was added. The solvent was distilled off under reduced pressure,whereby the title compound was obtained (yield: 47 g; 100%) NMR (CDCl₃,δ): 1.23-1.30(6 H,m), 1.54-1.57 (3 H,m), 2.90(6 H,s), 3.49,3.81(1H,ABq,J=17.0 Hz), 3.50,3.80(1 H,ABq, J=17.2 Hz), 4.86-5.29(5 H,m),6.83-6.86(1 H,m)

EXAMPLE 57 1-(Isopropoxycarbonyloxy)ethyl7-(4-bromo-3-oxobutyrylamino)-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR151##

After diketene (0.92 ml) was dissolved in methylene chloride (10 ml),the resulting solution was cooled to -30° C. and stirred. The reactionmixture was added dropwise with a methylene chloride solution (3 ml)containing bromine (0.66 ml) to prepare 4-bromo-3-oxobutyric acidbromide.

On the other hand, 1-(isopropyloxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate (5.05 g)was dissolved in methylene chloride (60 ml) together withbistrimethylsilylacetamide (5.8 ml). The resulting solution was addeddropwise with the 4-bromo-3-oxobutyric acid bromide solution, which hadbeen obtained above, at -30° C., followed by stirring for one hour underice cooling. The reaction mixture was washed successively with water andsaturated sodium chloride solution, followed by drying over anhydrousmagnesium sulfate and then by concentration under reduced pressure. Theconcentrate was subjected to chromatography on a column packed with 150g of silica gel, whereby the title compound was obtained (yield: 4.8 g;68.9%). NMR (CDCl₃, δ): 1.28-1.34(6 H,m), 1.59(3 H,d,J=5 Hz), 2.92(6H,s), 3.49,3.88(2 H,ABq,J=19 Hz), 3.51-3.75(2 H,m), 4.03-4.07(2 H,m),4.85-5.27(4 H,m), 5.80-5.90(1 H,m), 6.91(0.5 Hq,J=5 Hz), 7.00(0.5H,q,J=5 Hz)

EXAMPLE 58 1- (Isopropoxycarbonyloxy)ethyl7-(4-bromo-3-oxo-2-hydroxyiminobutyrylamino)-3-N,N-dimethylcarbamoyloxyethyl-3-cephem-4-carboxylate##STR152##

The compound (4.5 g), which had been obtained in Example 57, wasdissolved in acetic acid (45 ml) and the resulting solution was addedwith sodium nitrite (0.58 g) under ice cooling, followed by stirring atroom temperature for one hour. The reaction mixture was added with ethylacetate. The resulting mixture was washed with water and a saturatedsodium chloride solution, followed by drying over anhydrous magnesiumsulfate and then by concentration under reduced pressure. Theconcentrate was subjected to chromatography on a column packed with 100g of silica gel, whereby the title compound was obtained (yield: 3.76 g;79.6%). NMR (CDCl₃, δ): 1.30-1.34(6 H,m), 1.56-1.61(3 H,m), 2.93(6 H,s),3.50-3.68(3 H,m), 4.54(2 H,s), 4.87-5.30(4 H,m), 5.84-5.90(1 H,m),6.92(0.5 H,q,J=5.5 Hz), 7.01(0.5 H,q, J=5.5 Hz), 9.40-9.45(1 H,m)

EXAMPLE 59 1-(Isopropyloxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR153##

The compound (1.0 g), which had been obtained in Example 58, wasdissolved in dimethylacetamide (15 ml) and the resulting solution wasadded with thiourea (0.244 g), followed by stirring at 5° C. for 12hours. The reaction mixture was added with ethyl acetate (200 ml). Theresulting mixture was washed with water and saturated sodium chloridesolution, followed by drying over anhydrous magnesium sulfate and thenby concentration under reduced pressure. The concentrate was dissolvedin ethyl acetate (10 ml). The resulting solution was added dropwise toisopropyl ether (150 ml) under stirring. The resulting precipitate wascollected by filtration and then dried, whereby the title compound wasobtained (yield: 0.6 g; 62.3%). NMR (CDCl₃, δ): 1.26-1.37(6 H,m),1.58-1.62(3 H,m), 2.93(6 H,s), 3.50(1 H,d,J=19 Hz), 3.60,3.61(together,1 H,d, J=19 Hz), 4.9-5.24(3 H,m), 5.04,5.07(together, 1 H,d,J=5 Hz),5.93(1 H,dd,J=5 Hz,8 Hz), 6.92,7.02(together, 1 H,q,J=5.5 Hz), 7.08 (1H,s)

EXAMPLE 60 1-(Isopropoxycarbonyloxy)ethyl7-[4-chloro-3-oxobutyrlamino)-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR154##

Diketene (21 ml) was dissolved in methylene chloride (60 ml), followedby cooling to -30° C. Chlorine gas was spurged through the resultingsolution until the latter turned to a pale yellow color. Excess chlorinewas purged out with nitrogen gas, and in addition, methylene chloridewas distilled off under reduced pressure. The residue was distilled,whereby 4-chloro-3-oxoburyric acid chloride having a boiling point of75°-85° C. (8 mm/Hg) was obtained (7.1 g).

On the other hand, 1-(isopropyloxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate ester (3g) was dissolved in methylene chloride (45 ml). The resulting solutionwas added with N,N-dimethylaniline (0.98 ml) under ice cooling, followedby stirring. The reaction mixture was added dropwise with a solution of4-chloro-3-oxybutyric acid chloride (1.2 g), which had been obtainedabove, in methylene chloride (15 ml) at -30° C. After the resultingsolution was stirred for one hour under ice cooling, the reactionmixture was washed successively with water and saturated sodium chloridesolution, followed by drying over anhydrous magnesium sulfate and thenby concentration under reduced pressure. The concentrate was subjectedto chromatography on a column packed with 70 g of silica gel, wherebythe title compound was obtained (yield: 0.59 g: 25.1%). NMR (CDCl₃, δ):1.29-1.33(6 H,m), 1.58(3 H,d,J=5 Hz), 1.58(1.5 H,s), 1.59(1.5 H,s),2.92(6 H,s), 3.46-4.26(6 H,m), 4.85-5.35(4 H,m), 5.80-5.87(1 H,m),6.90(0.5 H,q,J=5 Hz), 6.99(0.5 H,q,J=5 Hz), 7.53(0.5 H,q,J=9 Hz),7.61(0.5 H,q,J=9 Hz)

EXAMPLE 61 1-(Isopropoxycarbonyloxy)ethyl7-(4-chloro-3-oxo-2-hydroxyiminobutyrylamino)-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR155##

The compound (0.5 g), which had been obtained in Example 60, wasdissolved in methylene chloride (5 ml) and then, acetyl chloride (0.092ml) and isoamyl nitrite (0.167 ml) were added to the resulting solutionat room temperature. At the same temperature, the resulting solution wasstirred for 5.5 hours. The reaction mixture was washed with water andsaturated sodium chloride solution, followed by drying over anhydrousmagnesium sulfate and then by concentration under reduced pressure. Theconcentrate thus obtained was subjected to chromatography on a silicagel column, whereby the title compound was obtained (yield: 0.48 g;77.3%) NMR (CDCl₃, δ):

1.29-1.34(6 H,m), 1.59(3 H,d,J=5.5 Hz), 2.93(3 H,s), 3.51-3.66(2 H,m),4.78(2 H,s), 4.82-4.98(1.5 H,m), 5.14-5.31(1.5 H,m), 5.05-5.08(1 H,m),5.84-5.90(1 H,m), 6.91(0.5 H,q,J=5.5 Hz), 7.00(0.5 H,q,J=5.5 Hz),9.35-9.40(1 H,m)

EXAMPLE 62 1-(Isopropoxycarbonyloxy)ethyl7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR156##

The compound (0.48 g), which had been obtained in Example 61, wasdissolved in dimethylacetamide (7 ml). The resulting solution was addedwith thiourea (0.126 g), followed by stirring at 5° C. for 16 hours. Thereaction mixture was added with ethyl acetate (80 ml). The resultingmixture was washed with water and an aqueous sodium chloride solution,followed by drying over anhydrous magnesium sulfate and then byconcentration under reduced pressure. The precipitate was dissolved inethyl acetate (5 ml) and the resulting solution was added dropwise toisopropyl ether (70 ml) under stirring. The precipitate was collected byfiltration and dried, whereby the title compound was obtained (yield:0.252 g; 50.6%). NMR and HPLC data of the compound obtained in thisexample were consistent with those of the compound obtained in Example59.

EXAMPLE 63 Benzhydryl7-formamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylateester ##STR157##

Benzhydryl 7-formamido-3-hydroxymethyl-3-cephem-4-carboxylate ester (106g) and p-nitrophenyl chloroformate (50.4 g) were stirred intetrahydrofuran (700 ml) under ice cooling. To the resulting suspension,pyridine (19.8 g) was added dropwise over 5 minutes. After 35 minutes,the mixture was poured into a mixed solvent of ethyl acetate (1 l) andwater (1 l). The organic layer was washed twice with water (0.5 ml) andonce with saturated sodium chloride solution, followed by drying overmagnesium sulfate. The solvent was distilled off under reduced pressureuntil its volume was decreased to about 400 ml. The residue wasgradually poured into isopropyl ether (2 l) and the resulting crystalswere collected by filtration, whereby the title compound was obtained(yield: 133 g; 90%). NMR (DMSO-d₆, δ): 3.67,3.77(2 H,ABq,J=18 Hz),4.91,5.11(2 H,ABq,J=12 Hz), 5.21(1 H,J=4.8 Hz), 5.91(1 H,dd,J=4.8 Hz,8.5Hz), 6.91(1 H,s), 7.2-7.5(12 H,m), 8.14(2 H,d,J=9 Hz), 8.31(2 H,d,J=9Hz), 9.11(1 H,d,J=8.5 Hz)

EXAMPLE 647-Formamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylic acid##STR158##

The compound (133 g), which had been obtained in Example 63, wassuspended in dichloromethane (265 ml) under stirring. To the suspension,trifluoroacetic acid (200 ml) was added dropwise over 25 minutes underice cooling. Ten 10 minutes later, the resulting suspension was pouredinto isopropyl ether (2.5 l). The resulting crystals were collected byfiltration and then washed with isopropyl ether, whereby the titlecompound was obtained (yield 103 g; 97.4%). NMR (DMSO-d₆, δ):3.62,3.72(2 H,ABq,J=18 Hz), 4.94,5.23(2 H,ABq, J=12.6 Hz), 5.15(1H,J=4.9 Hz), 5.81(1 H,dd, J=4.9 Hz,8.8 Hz), 7.56(2 H,d,J=9 Hz), 8.13(1H,s), 8.30(2 H,d,J=9 Hz), 9.07(1 H,d,J=8.8 Hz)

EXAMPLE 65 Benzhydryl7-thienylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylateester ##STR159##

Benzhydryl 7-thienylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate(1.6 g) and p-nitrophenylchloroformate (0.6 g) were treated in a similarmanner to Example 63, whereby the title compound was obtained [yield:2.3 g (stoichiometric)]. NMR (CDCl₃, δ): 3.43,3.62(2 H,ABq,J=19 Hz),4.85(2 H,s), 4.97,5.24 (2 H,ABq,J=13 Hz), 5.01(1 H,d,J=4.5 Hz), 5.91(1H,dd, J=4.5 Hz, 9 Hz), 6.93(1 H,s), 6.97-7.02(2 H,m), 7.24-7.38(11 H,m),7.42(2 H,d,J=8 Hz), 8.26(2 H,d,J=8 Hz)

EXAMPLE 667-Thienylacetamido-3-p-nitrophenoxycarbonyloxymethyl-3-cephem-4-carboxylicacid ##STR160##

The compound (1.4 g), which had been obtained in Example 65,trifluoroacetic acid (1 ml) and anisole (2 ml) were stirred for 30minutes under ice cooling. The reaction mixture was added with isopropylether (50 ml) and the resulting precipitate was collected by filtration,whereby the title compound was obtained (yield: 900 mg; 85%) NMR (CD₃OD, δ): 3.57,3.73(2 H,ABq,J=19 Hz), 3.80(2 H,s), 5.06,5.33 (2 H,ABq,J=12Hz), 5.09(1 H,d,J=4.5 Hz), 5.77(1 H,d, J=4.5 Hz), 6.9-7.0(2 H,m),7.23-7.28(1 H,m), 7.46(2 H,d,J=8 Hz), 8.29(2 H,d,J=8 Hz)

EXAMPLE 67 Benzhydryl7-formamido-3-phenoxycarbonyloxymethyl-3-cephem-4-carboxylate ##STR161##

In a similar manner to Example 63 except that p-nitrophenylchloroformate was replaced by phenyl chloroformate, the title compoundwas obtained (yield 90%). NMR (DMSO-d₆, δ): 3.66,3.75(2 H,ABq,J=19 Hz),4.85,5.05(2 H,ABq,J=14 Hz), 5.21(1 H,d,J=4.5 Hz), 5.91(1 H,dd,J=4.8 Hz,8Hz), 6.90 (1 H,s), 7.17-7.50(15 H,m), 8.14(1 H,s), 9.11 (1 H,d,J=8 Hz)

EXAMPLE 68 7- Formamido-3-phenoxycarbonyloxymethyl-3-cephem-4-carboxylicacid ##STR162##

The compound, which had been obtained in Example 67, was treated in asimilar manner to Example 64, whereby the title compound was obtained(yield 90%). NMR (DMSO-d₆, δ): 3.61,3.72(2 H,ABq,J=18 Hz), 4.89,5.19(2H,ABq,J=12 Hz), 5.14(1 H,d,J=4.5 Hz,8 Hz), 7.20-7.45(5 H,m), 8.12(1H,s), 9.06(1 H,d,J=8 Hz)

EXAMPLE 69 Sodium 7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate ##STR163##

The compound (103 g), which had been obtained in Example 64, wasdissolved in methanol (600 ml). Tetrahydrofuran (44 ml) containing 22 gof dimethylamine was added dropwise to the resulting solution over 5minutes under ice cooling. One hour later, the resulting solution wasadded with sodium acetate (24 g), followed by concentration underreduced pressure. To the residue, isopropyl alcohol (0.8 l) and thenisopropyl ether (1.5 l) were added, respectively. The resultingprecipitate was collected by filtration. The solid thus obtained wasdissolved in methanol (0.5 l). After the crystals were formed, isopropylether (1.5 l) was added and then, the resulting solution was filtered,whereby the title compound was obtained (yield: 72 g; 84%). NMR(DMSO-d₆, δ): 2.79(6 H,s), 3.22,3.46(2 H,ABq,J=17.2 Hz), 4.68,4.94 (2H,ABq, J=12.0 Hz), 4.96(1 H,d,J=4.8 Hz), 5.55(1 H,dd, J=4.8 Hz,9 Hz),8.10(1 H,s), 8.93(1 H,d,J=9 Hz)

EXAMPLE 707-Thienylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylicacid ##STR164##

The compound (100 mg), which had been obtained in Example 66, wasdissolved in N,N-dimethylformamide (1 ml). The resulting solution wasadded with a 50% aqueous solution of dimethylamine (50 mg) under icecooling, followed by reaction for 15 minutes. To the reaction mixture,ethyl acetate (50 ml) and water (30 ml) were added. Then, the organiclayer was collected, washed with water and saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was added with isopropyl ether. Theresulting solid was collected by filtration, whereby the title compoundwas obtained (yield: 60 mg; 75%). NMR (DMSO-d₆, δ): 2.82(3 H,s), 2.84(3H,s), 3.48,3.60(2 H,ABq,J=19 Hz), 3.78(2 H,s), 4.48,4.99(2 H,ABq,J=11Hz), 5.09(1 H, d,J=4.5 Hz), 5.64(1 H,dd,J=4.5 Hz,8 Hz), 6.92-7.00(2H,m), 7.38(1 H,d,J=3 Hz), 9.12(1 H,d,J=8 Hz)

EXAMPLE 71 Sodium7-formamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR165##

The compound, which had been obtained in Example 68, was treated in asimilar manner to Example 69, whereby the title compound was obtained(yield: 35%).

The compound obtained in this example conformed with the compoundobtained in Example 69 in all physicochemical properties such as HPLC(high performance liquid chromatography), TLC (thin-layerchromatography) and NMR spectrum.

PREPARATION EXAMPLE 49

Tert-butyl7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-1-oxide##STR166##

To a solution of tert-butyl7-phenylacetamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide (76.1 g;0.158 mol) in N,N-dimethylformamide (350 ml), ammonium trifluoroacetate(41.3 g; 0.316 mol) and sodium iodide (23.6 g; 0.158 mol) were added,followed by stirring at room temperature. The reaction mixture was addedwith ammonium trifluoroacetate (10.3 g; 0.079 mol) upon an elapsed timeof 4 hours and 35 minutes from the initiation of the stirring and thenwith sodium iodide (11.8 g, 0.079 mol) upon an elapsed time of 8 hoursand 5 minutes after the initiation of the stirring. Stirring wascontinued at room temperature for 24 hours and 25 minutes in total. Thereaction mixture was poured into a mixture of ethyl acetate, and waterand the ethyl acetate layer was collected. The water layer was extractedtwice with ethyl acetate. Ethyl acetate layers were combined together,successively washed with water and saturated aqueous sodium chloridesolution, and then dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure, whereby tert-butyl7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-1-oxide wasobtained (yield: 63.5 g; 96.1%). NMR (CDCl₃, δ): 1.58(9 H,s), 3.00(1H,br.s), 3.17,3.94(2 H,ABq, J=18.7 Hz), 3.62(2 H,s), 4.13,4.47 (2H,ABq,J=13.2 Hz), 4.42(1 H,d,J=4.8 Hz), 6.02(1 H,dd,J=4.8 Hz,9.7 Hz),6.90(1 H,d,J=9.7 Hz), 7.24-7.30(5 H,m)

PREPARATION EXAMPLE 50 Tert -butyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide##STR167##

To a solution of tert-butyl7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-1-oxide (63.5g; 0.151 mol) in tetrahydrofuran (500 ml), N,N'-carbonyldiimidazole(24.5 g; 0.151 mol) was added under ice cooling, followed by stirring atthe same temperature for 50 minutes. The reaction mixture was pouredinto a mixture of ethyl acetate and water and the ethyl acetate layerwas collected. The ethyl acetate layer was washed successively withwater and a saturated aqueous sodium chloride solution and then driedover magnesium sulfate. The drying agent was filtered off and thefiltrate was added with a 50% aqueous solution of dimethylamine (13.6 g;0.151 mol) under ice cooling. Without changing the temperature, thestirring was continued for 3 hours and 45 minutes. The reaction mixturewas poured into a mixture of ethyl acetate and 1N hydrochloric acid,followed by the collection of the ethyl acetate layer. The water layerwas extracted further with ethyl acetate. Both ethyl acetate layers werecombined together and washed successively with water and saturatedaqueous sodium chloride solution, followed by drying over magnesiumsulfate. Then, the solvent was distilled off under reduced pressure. Theresidue was purified by chromatography on a silica gel column, wherebytert-butyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxidewas obtained (yield: 15.8 g; 21.2%). NMR (δ, CDCl₃): 1.13(9 H,s), 2.88(3H,s), 2.89(3 H,s), 3.17,3.80 (2 H,ABq,J=19.0 Hz), 3.62(2 H,s), 4.42(1H,d,J=4.8 Hz), 4.70,5.31(2 H,ABq,J=14.1 Hz), 6.03 (1 H,dd,J=4.8 Hz, 9.9Hz), 6.77(1 H,d,J=9.9 Hz), 7.25-7.36(5 H,m)

PREPARATION EXAMPLE 51 Tert-butyl7-Phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR168##

To a solution of tert-butyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate-1-oxide(15.8 g; 0.0322 mol) in N,N-dimethylformamide (120 ml), phosphorustrichloride (8.4 ml; 0.0963 mol) was added dropwise over 5 minutes underdry ice-methanol cooling so that the solution temperature did not risebeyond -15° C. Then, stirring was continued for 20 minutes under dryice-methanol cooling. After the reaction mixture was diluted with ethylacetate, water was added gradually to the mixture under dry ice-methanolcooling so that the liquid temperature did not rise beyond -10° C. Theethyl acetate layer was collected and the water layer was extractedfurther with ethyl acetate. Both ethyl acetate layers were combinedtogether and washed successively with water and saturated aqueous sodiumchloride solution, followed by drying over magnesium sulfate. Then, thesolvent was distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column, whereby tert-butyl 7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (9.3 g; 60.8%). NMR (δ, CDCl₃): 1.48(9 H,s), 2.88(3 H,s),2.89(3 H,s), 3.34,3.50 (2 H,ABq,J=18.5 Hz), 3.63(2 H,ABq,J=13.6 Hz),4.92(1 H,d,J=4.9 Hz), 4.77,5.09(2 H,ABq,J=13.6 Hz), 5.81(1 H,dd,J=4.9Hz,9.2 Hz), 6.19(1 H,d,J=9.2 Hz), 7.24-7.36(5 H,m)

PREPARATION EXAMPLE 52 Sodium7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate##STR169##

To a solution of tert-butyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(9.2 g) in anisole (4.5 ml) and dichloromethane (50 ml), trifluoroaceticacid (9 ml) was added dropwise under ice cooling. Four and a half hourslater, trifluoroacetic acid (18 ml) was added further dropwise at thesame temperature. Without changing the temperature, stirring wascontinued for 6 hours and 20 minutes in total from the beginning of thefirst dropwise addition. The reaction mixture was concentrated underreduced pressure, followed by the addition of diisopropyl ether. Thesupernatant was removed by decantation. The residue was dissolved inmethanol. To the resulting solution, sodium acetate (1.05 g) was added,followed by stirring until the resulting solution became a homogeneoussystem. The reaction mixture was added with diisopropyl ether. Theprecipitate was collected by filtration and, after washing withdiisopropyl ether, was dried under reduced pressure. The precipitate waspurified by ODS, whereby sodium7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (yield: 2.2 g; 25.8%). NMR (δ, D₂ O): 2.74(6 H,br.s),3.21,3.47(2 H,ABq,J=17.9 Hz), 3.51,3.57(2 H,ABq,J=14.8 Hz), 4.51,4.74(2H,ABq, J=12.6 Hz), 4.92(1 H,d,J=4.6 Hz), 5.48(1 H,d,J=4.6 Hz), 7.18-7.28(5 H,m)

PREPARATION EXAMPLE 53 1-(Isopropoxycarbonyloxy)ethyl7-phenylacetamido-3-(1-dimethylamino)carbonyloxymethyl-3-cephem-4-carboxylate##STR170##

To a solution of sodium7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(2.2 g; 0.005 mol) in N,N-dimethylformamide (20 ml),isopropyl-1-iodoethyl carbonate (1.29 g; 0.005 mol) was added all atonce under ice cooling, followed by stirring at the same temperature for30 minutes. The reaction mixture was poured into a mixture of ethylacetate and water, and the ethyl acetate layer was collected. The ethylacetate layer was washed successively with water and saturated aqueoussodium chloride solution, followed by drying over magnesium sulfate.Then, the solvent was distilled off under reduced pressure. The residuewas purified by chromatography on a silica gel column, whereby1-(isopropoxycarbonyloxy)ethyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatewas obtained (yield: 1.43 g; 52.1%). NMR (δ, CDCl₃): 1.22-1.29(6 H,m),1.26(3 H,d,J=4.9 Hz), 2.85(6 H,br.s), 3.35,3.48(1 H,ABq,J=18.4 Hz),3.36,3.49(1 H,ABq, J=18.4 Hz), 3.55(2 H,s), 4.75-4.88(3 H,m),5.04,5.10(1 H,ABq,J=13.9 Hz), 5.71-5.76(1 H,m), 6.77-6.82(1 H,m),6.91(0.5 Hq,J=5.5 Hz), 6.94(0.5 H,d,J=8.9 Hz), 7.19-7.29(5 H,m)

EXAMPLE 72 (Isopropoxycarbonyloxy)methyl7-β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylatehydrochloride ##STR171##

The compound, which had been obtained in Example 63, was reacted withiodomethylisopropyl carbonate, whereby the above compound was obtained(yield: 51%). NMR (CD₃ OD,δ): 1.29(6 H,m), 2.90(3 H,s), 2.92(3 H,s),3.55,3.71 (2 H,ABq,J=18 Hz), 4.78,5.13(2 H,ABq,J=14 Hz), 5.20(1 H,d,J=5Hz), 5.80(1 H,d,J=5 Hz), 5.90-5.97(1 H,m), 6.84(1 H,s)

EXAMPLE 73 (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl7β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyiminoacetamido]-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-carboxylatehydrochloride ##STR172##

The compound, which had been obtained in Example 63, was reacted with(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl iodide, whereby the titlecompound was obtained (yield: 49%). NMR (CD₃ OD,δ): 2.2(3 H,s), 2.87(3H,s), 2.92(3 H,s), 3.52,3.69 (2 H,ABq,J=18 Hz), 4.8-5.18(4 H,m), 5.20(1H,d,J=5 Hz)

EXAMPLE 74 1-(Isopropoxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(hydrochloride) ##STR173##

To a solution of phosphorus pentachloride (625 mg; 3 mmol) indichloromethane (10 ml), pyridine (237 mg; 3 mmol) was added at roomtemperature, followed by stirring for 20 minutes at the sametemperature. The reaction mixture was subjected to ice cooling, to whicha solution of 1-(isopropoxycarbonyloxy)ethyl7-phenylacetamido-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylate(549 mg, 1 mmol) in dichloromethane (10 ml) was added without changingthe temperature. Stirring was continued for one hour and 10 minutes. Thereaction mixture was cooled in a dry ice-methanol bath and added with1,4-butanediol (1 ml) and methanol (1 ml), followed by stirring for 30minutes. Further, water was added to the reaction mixture at the sametemperature. The reaction mixture was then diluted with water andextracted with ethyl acetate. The water layer was controlled to pH 6.5with a saturated aqueous solution of sodium hydrogencarbonate andextracted with ethyl acetate. The latter ethyl acetate layer was washedwith a saturated aqueous sodium chloride solution, followed by dryingover magnesium sulfate. The drying agent was filtered off and thefiltrate thus obtained was added with HCl-saturated ethyl acetate. Thesolvent was distilled off under reduced pressure, whereby1-(isopropoxycarbonyloxy)ethyl7-amino-3-N,N-dimethylcarbamoyloxymethyl-3-cephem-4-carboxylatehydrochloride was obtained (yield: 90 mg; 19.3%). NMR (δ, CD₃ OD):1.21-1.30(6 H,m), 1.52-1.55(3 H,m), 2.86-3.02(6 H,m), 3.70,3.78(1H,ABq,J=18.1 Hz), 3.77,3.82(1 H,ABq, J=13.7 Hz), 4.81-4.92(1 H,m),4.90,5.10(2 H,ABq, J=12.8 Hz), 5.11-5.23(0.5, m), 5.28-5.33(0.5, m),6.82-6.88(0.5, m), 6.91-6.97(0.5, m)

We claim:
 1. A 7-acyl-3-substituted carbamoyloxy cephem compoundrepresented by the following formula (1): ##STR174## wherein A means a--CH═ or --N═ group; R¹ denotes a hydroxyl group, a lower alkoxyl group,a fluorine-substituted lower alkoxyl group or a hydroxyl group protectedby a protecting group; R² and R³ are the same or different andindividually represent a lower alkyl group, a hydroxyl-substituted loweralkyl group, a carbamoyl-substituted lower alkyl group or acyano-substituted lower alkyl group, R² is a hydrogen atom and R³ is alower alkoxyl group or a lower alkyl group which may optionally besubstituted by one or more halogen atoms or the group represented by theformula ##STR175## means a 4-6 membered heterocyclic group, whichcontains one nitrogen atom, or a morpholino group, said heterocyclicgroup or morpholino group being optionally substituted by one or morelower alkyl, hydroxyl and/or hydroxyl-substituted lower alkyl groups;and R⁴ denotes a carboxyl group or a carboxyl group protected by aprotecting group; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein A means a --CH═ group.
 3. The compound ofclaim 1, wherein A means a --N═ group.
 4. The compound of claim 1,wherein R¹ is a hydroxyl group.
 5. The compound of claim 1, wherein theformula ##STR176## means a group ##STR177## --NHCH₃ or --N(CH₃)₂.
 6. Thecompound of claim 1, wherein R² and R³ are both methyl groups.
 7. Thecompound of claim 1, wherein R¹ is a hydroxyl or protected hydroxylgroup, and R² and R³ are both methyl groups.
 8. The compound of claim 1or 7, wherein R⁴ represents a carboxyl group or a carboxyl groupprotected by at least one group selected from the class consisting of1-(isopropyloxycarbonyloxy)ethyl group, 1-(ethoxycabonyloxy)ethyl group,1-(cyclohexyloxycarbonyloxy)ethyl group, pivaloyloxymethyl group andisopropyloxycarbonyloxymethyl group.
 9. The compound of claim 1 or 7,wherein R⁴ is a carboxyl group or a carboxyl group protected by1-(isopropyloxycarbonyloxy)ethyl group.